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Arthropod Structure & Development 35 (2006) 357e378 www.elsevier.com/locate/asd

Review

Markus Friedrich a,b,* b

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Ancient mechanisms of visual sense organ development based on comparison of the gene networks controlling larval eye, ocellus, and compound eye specification in Drosophila a Department of Biological Sciences, Wayne State University, 5047 Gullen Mall, Detroit, MI 48202, USA Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201, USA

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Received 15 May 2006; accepted 10 August 2006

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Abstract

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Key mechanisms of development are strongly constrained, and hence often shared in the formation of highly diversified homologous organs. This diagnostic is applied to uncovering ancient gene activities in the control of visual sense organ development by comparing the gene networks, which regulate larval eye, ocellus and compound eye specification in Drosophila. The comparison reveals a suite of shared aspects that are likely to predate the diversification of arthropod visual sense organs and, consistent with this, have notable similarities in the developing vertebrate visual system: (I) Pax-6 genes participate in the patterning of primordia of complex visual organs. (II) Primordium determination and differentiation depends on formation of a transcription factor complex that contains the products of the selector genes Eyes absent and Sine oculis. (III) The TGF-b signaling factor Decapentaplegic exerts transcriptional activation of eyes absent and sine oculis. (IV) Canonical Wnt signaling contributes to primordium patterning by repression of eyes absent and sine oculis. (V) Initiation of determination and differentiation is controlled by hedgehog signaling. (VI) Egfr signaling drives retinal cell fate specification. (VII) The proneural transcription factor atonal regulates photoreceptor specification. (VII) The zinc finger gene glass regulates photoreceptor specification and differentiation. Ó 2006 Elsevier Ltd. All rights reserved.

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Keywords: Drosophila; Eye development; Evolution of development; Gene regulatory network; Ocellus; Bolwig organ

1. Introduction

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Validating the notion that phenotypic evolution is, in its most basic form, the outcome of developmental gene network changes (Davidson, 2005), insights derived from comparisons of developmental gene activities have rewritten textbook pages. A dramatic example is the discovery of highly conserved gene activities in the development of functionally and phyletically vastly diverse eye types, which speaks for evolution

Abbreviations: BOL, Bolwig organ anlage; CEY, compound eye primordium; EAD, eye-antennal imaginal disc; EYD, eye disc; OCE, ocellus primordium. * Correspondence to: Department of Biological Sciences, Wayne State University, 5047 Gullen Mall, Detroit, MI 48202, USA. Tel.: þ1 313 577 9612; fax: þ1 313 577 6891. E-mail address: [email protected] 1467-8039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.asd.2006.08.010

from a single simple ancestral visual organ rather than multiple independent precursor organs (Gehring, 2002; Zuker, 1994). Understanding the genetic developmental organization of the ancestral structure from which these different eye types evolved is more than a fascinating glimpse into the past. It is crucial for determining the nature of developmental changes that shaped metazoan eye diversity. Such data are also likely to add to the increasing number of ancient gene regulatory modules that are being discovered as integral parts of the diversified developmental programs in the Metazoa (Garcia-Bellido, 1981; Huang, 1998; Rebeiz et al., 2005). Major efforts have been initiated to reconstruct the archetypical regulatory program of bilaterian visual organ development (Arendt and Wittbrodt, 2001; Pineda et al., 2000; Treisman, 1999, 2004). The most common approach for reconstructing ancestral traits is to compare homologous structures and processes between species. Eye developmental studies are

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extraretinal photoreceptors (Helfrich-Forster et al., 2002). Bolwig organs rank among the most rudimentary visual sense structures in insects (Bolwig, 1946). Each Bolwig organ consists of only one bundle of 12 photoreceptor cells (Fig. 1b). In the absence of any further accessory cells, the Bolwig organ facilitates phototactic behavior by using the cephalopharyngeal head skeleton, to which it is laterally attached, as a light screen. Circadian rhythm regulation is a second function carried out by the Bolwig organs (HelfrichForster et al., 2002; Malpel et al., 2002; Mazzoni et al., 2005). Due to the reduced need for sensitivity and resolution, the light harvesting compartments of the Bolwig organ photoreceptors consist of loosely organized lamellae in place of the highly stacked rhabdomeres of compound eye photoreceptors (compare Fig. 1b and e) (Melzer and Paulus, 1989). Reflecting the lack of image processing requirements, the Bolwig nerve does not project into a dedicated neuropil, but connects directly to circadian pace maker neurons in the larval and later adult brain (Malpel et al., 2002; Mazzoni et al., 2005; Meinertzhagen and Hanson, 1993). The structural simplicity of the Bolwig organs stands in dramatic contrast to the familiar sophistication of the adult Drosophila compound eyes (Fig. 1b and e) (for detailed review see Wolff and Ready, 1993; see also Callaerts et al., 2006). A single compound eye stores more than 6000 photoreceptors spread over 800 ommatidia. Each ommatidium is a self-sufficient optical unit equipped with eight photoreceptors, four cone cells and two primary pigment cells, optically insulated by secondary and tertiary pigment cells (Fig. 1e). Information received by the compound eye retina is processed in three serially connected optic neuropils: lamina, medulla and lobula (Meinertzhagen and Hanson, 1993). While biology and evolution of the larval and compound eyes are quite well understood, less is known regarding the ocelli. Most winged insects form three ocellida single median ocellus and a pair of lateral ocellidall of which are of identical cellular architecture (Fig. 1g) (for details see Yoon et al., 1996). A light diffraction apparatus is formed from a layer of epidermal corneagenous cells, which secrete a massive corneal lens that covers the entire retinal area. The corneagenous cells are sandwiched between the lens and the distal tips of the photoreceptors. Up to 95 densely packed rhabdomeric photoreceptors constitute the compact cup-shaped field of the ocellar retina. Sides and floor of the ocelli are wrapped by a thin monolayer of pigment cells. In contrast to the compound eye retina, no photoreceptor or pigment cell type diversity seems to exist in the ocelli. While molecular data may reveal yet unnoted cellular subtypes, it seems reasonable to assume that the ocelli represent a fundamentally simpler type of visual organ than the compound eye.

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therefore taking place in a wide range of species, including jellyfish, cephalopods, annelids, insects and vertebrates (for review see Gehring, 2004). There is nonetheless a strong bias towards analyses in the molecular genetic model organisms Drosophila, zebrafish and mouse. The comparison among these distantly related species has proven extremely informative due to the detail of advanced analysis (Chang et al., 2001; Donner and Maas, 2004). It, however, restricts the view to a small number of highly derived eye types, which may be associated with the loss or modification of ancestral pattern formation mechanisms (Arendt et al., 2002). A second approach for inferring ancient developmental mechanisms is the comparison of homologous structures within a species. This strategy has been used to investigate the developmental divergence of serially homologous appendages in arthropods (Averof and Patel, 1997; Casares and Mann, 1998; Giorgianni and Patel, 2004; Jockusch et al., 2004). Along similar lines, an ancestral genetic circuit underlying the control of sense organ differentiation has been unraveled by comparison of compound eye, stretch receptor and auditory organ development in the fruit fly Drosophila melanogaster Meigen, 1830 (Insecta, Pterygota) (Niwa et al., 2004). The latter work demonstrated that the evolutionary age and structural diversification of the Drosophila peripheral nervous system components offer a unique opportunity to dissect ancient mechanisms of developmental control. Adopting this approach, this review examines the specification of three highly diverged types of visual organs in Drosophila: the compound eyes and ocelli of the adult, and the Bolwig organs of the larva. Previous work suggests that the overlap of developmental genes expressed in the photoreceptor cells of these three organs is small reflecting their extensive evolutionary diversification (Treisman and Rubin, 1996). Therefore, most likely only extremely constrained and long-term conserved molecular genetic control mechanisms are identified as the cross-section of gene activities, which control the specification of these organs. The intention is to search for shared aspects between these gene networks in order to infer ancestral aspects of visual system development. The evolutionary significance of differences between the gene networks controlling larval and adult eye development is focus of a separate discussion (Friedrich, in press). Owing to space constraints, the review focuses on genes for which an ancient involvement in visual sense organ specification was found strongly supported or was previously proposed. A comprehensive overview of genes involved in Drosophila visual sense organ specification is given in Table 1. Additional data have been integrated in Fig. 3.

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2. The Drosophila visual sense organs 2.1. Morphology

2.2. Morphogenesis The headline that Drosophila commands over seven eyes still stirs a moment of skeptical surprise (Hofbauer and Buchner, 1989). The number results from summing up the two compound eyes and three ocelli of the adult, and the pair of larval Bolwig organs, which survive into the adult as

The development of ocellus (OCE), compound eye (CEY) and Bolwig organ primordia (BOL) is closely linked. The earliest precursor cells of all three organs trace back to the visual anlage, a field in the dorsal head neuroectoderm of

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Paulus, 1989, 2000). This is most clearly documented by the compound eye-like morphology of the larval eyes in primitive holometabolous insects (Paulus, 1989, 2000). It is further supported by similarities between larval eye morphogenesis in primitive holometabolous insects and embryonic compound eye development in primitive insects (Heming, 1982; Liu and Friedrich, 2004). The rudimentary morphology of the Bolwig organs is the result of a secondary reduction, which occurred during the evolution of larval acephaly (headlessness) leading to the maggot type larvae of the higher Diptera (Cyclorrhapha) (Melzer and Paulus, 1989). Thus, Bolwig organ and adult Drosophila compound eye diverged since the temporal and spatial decoupling of embryonic and postembryonic eye development in the ancestor of holometabolous insects (Friedrich, in press). Considering the oldest known fossils of holometabolous species, this implies at least 250 million years of diverging evolution (Kukalova´-Peck, 1991). The evolutionary origins of ocelli and compound eyes date back much deeper in time (for details see Bitsch and Bitsch, 2005). With the exception of Myriapoda, ocellus type both median eyes occur in representatives of all arthropod subphyla. The nauplius eyes of Crustaceans are considered homologous to the ocelli of insects (Paulus, 1972). The presence of median eyes and lateral compound eyes in the most primitive euchelicerate representative, the horseshoe crab Limulus, is further testimony of the age of arthropod median eyes (Jones et al., 1971). The origin of compound and median eyes thus likely predates the diversification of the arthropod subphyla. It thus seems safe to assume that this separation of these organs predates at least the Cambrium, which holds crustacean fossils, translating into over 500 million years of divergence. The evolution of ocelli and compound eyes from a single visual sense organ may have either occurred by organ duplication, as in the case of serially homologous eye structures, or by primordium partitioning, as in the case of the Bolwig organs (Oakley, 2003; Liu and Friedrich, 2004).

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the blastoderm embryo, from which all components of the visual system derive (Fig. 1a) (Green et al., 1993; Melzer and Paulus, 1989). Analysis of eye selector gene expression patterns revealed that the initially contiguous visual anlage separates into lateral halves during gastrulation (Fig. 1a) (Chang et al., 2001). This is followed by partitioning of each anlagen half into the primordia of the visual system organs (Fig. 1a) (Daniel et al., 1999; Green et al., 1993). The anlagen of the adult optic neuropils separate as invaginating optic placode. At the lateral edge of the optic placode, the differentiating BOL emerges as a single cluster of differentiating photoreceptor cells (Green et al., 1993; Schmucker et al., 1997). The visual anlage also contributes precursor cells to the eye-antennal imaginal disc (EAD), which invaginates dorsally of the BOL, and, importantly, receives cells from several embryonic head segments besides the visual anlage (YounossiHartenstein et al., 1993). During development of the larva, the EAD transforms from a monolayer cell sheet sack to a patchwork of differentiating head cuticle primordia (Fig. 1d) (for detailed review see Wolff and Ready, 1993; and also Callaerts et al., 2006). The compound eye retina develops in the posterior half of the EAD. This process becomes morphologically manifest after initiation of retina differentiation, it leading to the formation of a conspicuous differentiation zone, the morphogenetic furrow, which moves from the posterior margin of the eye field in anterior direction (Fig. 1d) (Ready et al., 1976; Wolff and Ready, 1993). Ommatidial development begins with the establishment of R8 photoreceptor founder cells at the posterior margin of the morphogenetic furrow (Wolff and Ready, 1991). Posterior to the furrow, retinal differentiation proceeds as ommatidia, seeded by regularly spaced R8 founder cells, form by sequential recruitment of photoreceptor, cone and pigment cells (Wolff and Ready, 1991). The EAD is also the place of ocellus development (Fig. 1d) (Garcia-Alonso et al., 1996). Two OCE form in the dorsal anterior field of each eye disc. The dorsal-most OCE from each EAD fuse to form the median ocellus. This process initiates at about the first half of the third larval instar to continue into pupation. The cellular dynamics of ocellus differentiation have not been studied in detail. It is therefore not known whether photoreceptor differentiation precedes that of corneagenous and pigment cells in the Drosophila ocelli. In primitive insects, the photoreceptors differentiate first, followed by the corneagenous and pigment cells (Goodman, 1981). This suggest a notable correspondence in the temporal sequence of basic cell type specification in the ocelli and the compound eye.

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2.3. Evolutionary origins and relationships Notwithstanding their simplicity, the Bolwig organs are evolutionarily younger than the ocelli and have closer ties to the compound eyes (Fig. 2). Developmental and genetic data argue that the Bolwig organs evolved from the partition of the arthropod compound eye, which is formed during embryogenesis in primitive insects (for detailed review see Friedrich, in press;

3. Transcription factors in Drosophila visual sense organ specification The determination of organ primordia results from the execution of specific developmental gene network scripts. Since this molecular dimension of development is best investigated for the CEY compared to the OCE and BOL, it will serve as a guideline. The progressing restriction of developmental competence via regional specification is a universal theme inthe development of metazoan organisms. It also applies to the gradual definition of the CEY in the Drosophila EAD by the spatial control of transcription factors acting as selector genes (for review see Curtiss et al., 2002). A main theme of this process is the integration of signaling pathway instructions and cis-regulatory interactions between the selector genes (Garcia-Bellido, 1975; Mann and Carroll, 2002; Mann and Morata, 2000). This logic recommends initiating the investigation by looking at the functions of selector genes in the Drosophila visual system.

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Fig. 1. Morphology and morphogenesis of Drosophila visual sense organs. (a) Schematics describing the development of the visual anlage based on Chang et al. (2001). The Drosophila embryonic head region is shown from the dorsal perspective. The visual anlage (VIS) originates as the dorsomedial field of neuroectodermal cells (S4), which separates into lateral halves during stage 5. In stage 12 embryos, the visual anlage divides into precursor tissues of different components of the Drosophila visual system including the outer optic lobe anlagen (OLAo) that will form lamina and medulla, the inner optic lobe anlage (OLAi), which forms the lobula neuropil, the anlage of the larval eye or Bolwig organ (OCE), and part of the eye-antennal imaginal disc (EAD). Approximate relative positions of visual system primordia are shown in the right inset. The Bolwig organ anlarge starts at the ventral edge of the visual anlarge. It moves inside the larval head during head

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Field specific selector genes are characterized by early and inclusive expression and upstream positions in developmental regulatory gene networks (Bessa et al., 2002; Davidson, 1991; Dominguez and Casares, 2005; Kenyon et al., 2003; Kumar and Moses, 2001a). These characteristics apply to three genes in the Drosophila visual system: the Pax-6 paired domain transcription factor genes eyeless (ey), its paralog twin of eyeless (toy), and the homeobox transcription factor gene orthodenticle (otd ) (Czerny et al., 1999; Finkelstein et al., 1990; Quiring et al., 1994). The discussion begins with ey and toy, which are the primordial eye selector genes in Drosophila both from a mechanistic as well as a historical point of view (see also Callaerts et al., 2006). Ey and toy are among the earliest selector genes expressed in the EAD. Their expression is detected in the nascent EAD shortly after invagination from the visual anlagen neuroectoderm (Chang et al., 2001; Czerny et al., 1999; Quiring et al., 1994). Both genes are initially expressed throughout the entire EAD. During the second larval instar, ey and toy expression clears from the antennal disc compartment and becomes specific to the ‘‘eye field’’, which is equivalent to the eye disc (EYD) compartment of the EAD that encompasses large regions of the dorsal and ventral head including the ocelli (Fig. 1d) (Haynie and Bryant, 1986; Kenyon et al., 2003). After onset of CEY differentiation, ey and toy are downregulated posterior to the morphogenetic furrow (Czerny et al., 1999; Quiring et al., 1994). This indicates that the presence of these field selector genes is specific for maintaining developmental competence to an extent that their expression is incompatible with the actual initiation of differentiation. Consistent with roles as eye field selector genes, toy and ey function at the highest levels of the gene network that regulates the specification of the CEY (Fig. 3a) (Czerny et al., 1999). The core of this network is built by a transcriptional activation

cascade, which is stabilized by feedback activation and also involves physical transcription factor interactions (Fig. 3a). Most members of this regulatory gene network core are characterized by necessity and sufficiency for the induction of compound eye development. Genetic elimination results in compound eye loss, while ectopic overexpression of individual genes or combinations thereof induces ectopic compound eye structures (Chen et al., 1997; Czerny et al., 1999; Halder et al., 1995; Pan and Rubin, 1998; Pignoni and Zipursky, 1997; Seimiya and Gehring, 2000; Shen and Mardon, 1997). The possibility of eye induction outside the eye field was first discovered in misexpression experiments with ey (Halder et al., 1995). Toy performs in the same assay with lower penetrance, but functions as a direct activator of ey during normal development (Fig. 3a) (Czerny et al., 1999). Ey is unable to activate the expression of toy or itself. Its expression, however, becomes independent from toy after initiation due to the positive feedback regulation by downstream members of the CEY determination gene network (Fig. 3a) (Czerny et al., 1999; Hauck et al., 1999). Published expression patterns suggest that ey and toy are also present in the region of the eye disc, where ocellus development occurs (Bessa et al., 2002; Czerny et al., 1999; Quiring et al., 1994; Royet and Finkelstein, 1996). The available information is, however, insufficient with regards to whether their expression is downregulated once OCE differentiation initiates as it does in the CEY. Genetic data reveal a differential requirement of ey and toy for ocellus and compound eye development (compare Fig. 3a and b). Ey null mutants lack compound eyes but possess normal ocelli, whereas a partial loss of ocelli but not compound eye is seen in toy null mutant flies surviving into adulthood (Punzo et al., 2002). Further consistent with a specific role of toy in ocellus development, an OCE specific enhancer element of the downstream selector gene sine oculis (so) is directly activated by Toy but not Ey (Fig. 3b) (Punzo et al., 2002). Nonetheless, although OCE and CEY differ in their sensitivity to ey and toy reduction, the combined data imply that the specification of both primordia depends on Pax-6 gene activity (Fig. 3d).

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3.1. Pax-6 genes execute field selector gene functions essential for the patterning of complex visual organs

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involution, and comes to rest as an attachment at the cephalopharyngeal head skeleton (see panels b and c) (Green et al., 1993). (b) Morphology of the Bolwig organ based on Melzer and Paulus (1989). The distal termini of the Bolwig organ photoreceptors (PHO) form lamelli like structures (LAM) that are attached to the tentorial phragma (TP) of the cephalopharyngeal head skeleton (CEP) via contacts with the inverted ectoderm. (BN, Bolwig nerve; IM, inner membrane). (c) Position of Bolwig organs (BO) and eye-antennal disc in the anterior head of the Drosophila larva. Schematic shows dorsally leveled longitudinal section of anterior larval body at second instar. The Bolwig nerve projects from the Bolwig organ at the cephalopharyngeal head skeleton into the larval brain (LB). Before entering the Bolwig nerve passes underneath the eye-antennal imaginal disc. CNS, central nervous system. (d) Schematic representation of eye-antennal imaginal disc morphogenesis. Continuous growth of the eye-antennal disc during the larval development produces the cellular material from which large parts of the adult head will be formed. The homogenous field of the first instar eye-antennal imaginal disc (10 ) separates into morphologically distinct antennal (AF) and eye disc (EYF) during the second larval instar (20 ). In the third instar larva (30 ), antennal primordium (AD) and compound eye primordium (CED) comparbments begin to differentiate. Retinal differentiation is headed by the morphogenetic furrow (MF). The anterior border of the pre-proneural domain (PPN) in front of the morphogenetic furrow is indicated by the grey-hatched outline. The curved black hatched outline represents emerging tissue folds in the anterior eye disc. The ocelli primordia (OCE) form in the anterior dorsal quadrant of the eye disc (drawings based on Cho et al., 2000; Haynie and Bryant, 1986; Wolff and Ready, 1993). (e) Schematic of the cellular architecture of the Drosophila retina based on Wolff and Ready (1993). 10 PC, primary pigment cell; 20 PC, secondary pigment cell; CC, cone cell; COR, cornea; PSE, pseudocone; PHO 1e6, outer photoreceptor cell body corresponding to one of photoreceptor cells 1e6; RHA 1e6, rhabdomere of one of the outer photoreceptor cells; RHA 7, distally restricted rhabdomere of photoreceptor cell 7; RHA 8, proximally restricted rhabdomere of photoreceptor cell 8. (f) Schematic presentation of dorsal adult head cuticle regions. The median (OCm) and lateral ocelli (OCl) are situated in the triangular ocellar field (OCF). The OCF is in the median center of the dorsal head cuticle. It is separated from the compound eye retina (CE) by frontal cuticle (FRO) and orbital cuticle (ORB) regions. (g) Schematic of the cellular architecture of Drosophila ocelli based on Yoon et al. (1996) and Garcia-Alonso et al. (1996). A massive cornea overlays the thin layer of corneagenous cells (COC). The distal tips of the ocellar photoreceptors directly contact the corneagenous cell layer. The ocellar photoreceptors fasciculate at the floor of the ocellar retina with the second order neurons of the ocellar nerve (ON). The ocellar retina is enclosed by a single layer of pigment cells (PC). Coordinates: a, anterior; d, dorsal, dis, distal; l, lateral; m, median; p, posterior; prox, proximal; v, ventral.

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Fig. 2. Origins and evolutionary relationships of Drosophila visual sense organs. Presumed organ multiplication events underlying the diversification of the Drosophila ocelli, Bolwig organs and compound eyes mapped on a phylogenetic tree. Branch lengths do not reflect relative times of divergence. Shared aspects of the Drosophila compound eye retina and ocelli are most parsimoniously explained by the presence in the precursor to these organs. The precursor structure of arthropod visual sense organs is therefore envisioned to have incorporated photoreceptor cells, pigment cells (brown) and a specialized epithelial cell layer (light blue) forming a cuticle lens (dark blue). Simple cup eye type visual sense organs are more widespread among basal Metazoans than compound eyes (Arendt and Wittbrodt, 2001). It is therefore reasonable to assume that the ocellus type of visual sense organ morphology corresponds more closely to the ancient precursor visual organ than the more complex compound eye. The ancient arthropod visual sense organ precursor may have been similar to the assembly of photoreceptor, lens and pigment cells proposed previously as ancestral visual organ of the Metazoa (Hartenstein and Reh, 2002). An organ duplication or partitioning event predating the emergence of arthropod subphyla at least 500 million years ago led to the diverging evolution of ocellus- and compound eye-like precursor structures. The evolution of holometabolous development resulted in spatial separation of the compound eye field developed during embryonic development (indicated by orange photoreceptor cells) from that developed during postembryonic development (indicated by red photoreceptor cells). The Drosophila compound eye is the structurally conserved derivative of the postembryonic partition of the ancestral compound eye. The evolution of the Bolwig organs from the embryonic partition of the ancestral compound eye involved reduction and fusion of single ommatidia, and reduction of ommatidial lens and pigment cells (Paulus, 1989, 2000).

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Consistent with a conserved function in eye field specification, toy is also the earliest and most widely expressed selector gene in the embryonic visual anlage (Czerny et al., 1999). Surprisingly, ey is not expressed in the early visual anlage despite the presence of toy (Chang et al., 2001; Czerny et al., 1999). Further analysis of the mechanisms underlying ey activation in the embryonic head confirms that the activation of ey by toy in the EAD is not in effect in the visual anlage (Adachi et al., 2003). Ey expression initiates in the developing mushroom bodies and other areas of the cephalic central nervous system, which overlap little with areas that express toy (Daniel et al., 1999; Kammermeier et al., 2001; Noveen et al., 2000). The co-expression of ey by toy in the nascent EAD is fairly unique among the derivatives of the visual anlage (Adachi et al., 2003; Czerny et al., 1999). No expression of toy is observed in the differentiating Bolwig organ itself and conflicting reports exist regarding the expression of ey (Daniel et al., 1999; Quiring et al., 1994; Sheng et al., 1997). The BOL precursor cells, however, can be assumed to experience a time window of transient toy

expression considering the expression of toy in early visual anlage (Czerny et al., 1999). Nonetheless, genetic evidence suggests that neither ey nor toy is an essential aspect of BOL development. Normal Bolwig organs form in ey and toy double deficient embryos (Suzuki and Saigo, 2000). The apparent Pax-6 independence of the BOL specification gene network marks one of the most dramatic differences to that of the CEY (compare Fig. 3a and c). The shared need of Pax-6 activation during CEY and OCE development is consistent with the substantial body of data that supports a universal upstream role of Pax-6 in animal eye development (Gehring, 2002). How can then the dispensability of ey and toy for Bolwig organ development be explained? Examples of Pax-6 independent visual organ development also exist in other animal groups. The Joseph cells and organs of Hesse, small visual organs of the lancelet fish, develop without expressing Pax-6 (Glardon et al., 1998). These data could suggest that visual organs, which consist of only a few photosensitive cells, tolerate a lack of Pax-6 selector gene activity. Data on Pax-6 in the annelid Platynereis dumerilii, however,

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the EAD. Subsequently, expression becomes restricted to the dorsal disc margin forming a protein gradient, which peaks at the dorsal edge (Royet and Finkelstein, 1995). The importance of otd for ocellus development is documented by the allele ocelliless, in which the specific loss of otd activation in the OCE leads to replacement of the ocelli with more ventral cuticle structures (Royet and Finkelstein, 1995). This phenotype implies that otd regulates dorsal EAD fates as a selector gene in a concentration-dependent manner. The upstream position of otd in the OCE determination gene network is linked with acting as a repressor in the CEY determination gene network (compare Fig. 3a and b). This is indicated by the replacement of retinal tissue with dorsal head cuticle as a result of misexpression of the signaling factor gene wingless (wg), which is associated with ectopic otd expression in the transformed CEY areas (Royet and Finkelstein, 1997). Although it remains to be tested if otd itself perturbs CEY specification, expression pattern and genetic data at the very least rule out that otd is necessary for CEY determination (Royet and Finkelstein, 1995). The situation is less clear with regards to the significance of otd for BOL specification in the embryo. Otd deficient embryos lack the segmentation gene domains and sensory structures of the antennal and ocular segments which include the Bolwig organs (Cohen and Jurgens, 1990; Schmidt-Ott et al., 1994). Since this phenotype is not associated with the replacement of head structures unlike in the EAD, the role of otd in the embryonic head appears to be of a gap segmentation gene rather than of a homeotic specification gene (Cohen and Jurgens, 1990). Consistent with this, otd misexpression experiments in the embryo generate patterning defects, which result from disturbing the function of pair rule genes instead of imposing primordium specification programs (Gallitano-Mendel and Finkelstein, 1998). The expression of otd becomes restricted to the protocerebral CNS during later embryonic development (Gallitano-Mendel and Finkelstein, 1998). This expression aspect is highly conserved in other arthropod species and vertebrates (Browne et al., 2006; Hartenstein and Reh, 2002; Li et al., 1996; Reichert and Simeone, 1999). The lack of otd expression in the developing BOL at this stage points against a specific involvement in BOL specification (Chang et al., 2001). Otd expression is detected at a later stage in the differentiating Bolwig organ photoreceptors. This aspect is shared with the compound eye and ocellus photoreceptors, but reflects a potentially ancient role in the control of photoreceptor differentiation, which is not related to primordium specification (Vandendries et al., 1996). In summary, the available data favor the view that otd performs OCE specific selector gene functions as part of its function as dorsal selector gene in the adult head.

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contradict this hypothesis. Pax-6 is persistently expressed in the Platynereis larval eye, which consists of a single photoreceptor cell and a single pigment cell, but not during development of the larger and cell type richer adult eye (Arendt et al., 2002). Further evidence against a correlation between Pax-6 involvement and eye size is the regeneration of eyespots in flatworms, which is not affected by Pax-6 knockdown (Callaerts et al., 1999; Pineda et al., 2002). It might be of significance that much of the size of the annelid and planarian adult eyes is reached by continuous differentiation from a stem cell zone, whereas the initial embryonic primordium is very small (Arendt et al., 2002). However, in the mouse, Pax-6 is involved during both patterning of the embryonic primordium as well as postembryonic regulation of retinal stem cells (Purcell et al., 2005). In the absence of obvious functional correlation, an independent acquisition of visual sense organ patterning roles by Pax-6 during evolution must be considered. Compatible with this is the proposal that Pax-6 was initially a regulator of structural visual sense organ genes such as rhodopsins and that functions in early patterning evolved later (Sheng et al., 1997). Several aspects of ey and toy function in the Drosophila CEY further support the idea that Pax-6 is specifically required for the build-up of large fields of eye fate biased cells in this species: (I) the restriction of ey and toy to the anterior proliferating region of the eye field speaks in favor of a model in which Pax-6 is essential for the regulation of primordium growth but not differentiation. This characteristic is paralleled in vertebrates where Pax-6 expression is specific for undetermined tissue associated with the developing eye (Marquardt et al., 2001). (II) Ey is likely to form a transcription factor complex with the products of the genes teashirt (tsh) and homothorax (hth), which maintains the proliferative area in the anterior EYD (Fig. 3a) (Bessa et al., 2002). (III) Dramatic loss of head tissue phenotypes of strong Drosophila toy and ey mutants further indicate a function of ey and toy in facilitating proper cell tissue proliferation in the EAD (Kronhamn et al., 2002). It has been argued that ey functions as an ocular segment selector gene instead of a sensu stricto retinal determination gene based on the observation that proneural gene expression is initiated in growth rescued ey null mutant EYD (Niwa et al., 2004). Further backing a broader role of ey in the patterning of head organ primordia is its role in the determination of the maxillary palp in antagonistic interaction with the Hox gene proboscipedia (Benassayag et al., 2003). Controlling proper proliferation and specification of the CEY and OCE may be conserved subfunctions of an ancient role in metamer-wide patterning. Two obvious factors may have led to the dispensability of ey and toy for BOL development: (I) reduced organ patterning and (II) reduced growth during the highly derived development of the Drosophila acephalic larval head.

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3.2. An ocellus field selector gene: orthodenticle A key regulator of OCE specification is the paired-like homeobox transcription factor gene otd (Royet and Finkelstein, 1995). Otd expression begins in the second instar throughout

3.3. Universal requirement of the early retinal genes sine oculis and eyes absent for Drosophila sense organ development Pax-6 mediated specification of the eye field lays the ground for the specification of the CEY proper. This occurs via

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Fig. 3. The developmental gene networks regulating Drosophila visual sense organ formation. Green: primordium promoting gene interactions. Red: primordium antagonizing gene activities. Bold arrowheads indicate direct activation. Open arrowheads represent epistatic interaction which may be direct or indirect. Hatched arrows indicate interactions hypothesized based on expression patterns and comparative evidence. Genes in parentheses represent cases in which expression appears likely or possible but needs to be confirmed. Transcription factors that form complexes are enclosed by framed background. Green background indicates transcription factor complexes that promote visual sense primordium determination. Orange background indicates transcription factor complexes that promote visual sense primordium proliferation. (a) Regulatory gene network of compound eye primordium development. A protein complex formed by the early retinal gene products Eya, So and Dac form the core of the network preparing cells to enter retinal differentiation (Chen et al., 1997; Pignoni et al., 1997). The early retinal genes are activated by the Pax-6 paralogs toy and ey. Toy is epistatic to ey but synergizes with ey in transcriptional activation of so (Halder et al., 1998; Niimi et al., 1999; Punzo et al., 2002). Ey has been shown to activate all early retinal genes directly (Halder et al., 1998; Niimi et al., 1999; Ostrin et al., 2006; Pappu et al., 2005; Punzo et al., 2002). Primary target of ey activation among the early retinal genes is eya (Halder et al., 1998). The activation of eya further depends on stimulation by Dpp signaling and the expression of tsh (Bessa and Casares, 2005; Halder et al., 1998). The onset of Dpp expression is dependent on Hh (Pignoni and Zipursky, 1997; Royet and Finkelstein, 1997). Activating effects of the early retinal genes on ey generate an autoregulatory positive feedback loop that stabilizes eye specification gene expression (Desplan, 1997). Prior to the activation of cell determination in conjunction with Dpp, ey is coexpressed with tsh and the compound eye primordium antagonistic transcription factor hth (Bessa and Casares, 2005). Tsh binding of Hth and Ey precipitates a transcription factor complex that biases cells towards compound eye primordium fate but maintains a proliferative state (Bessa and Casares, 2005). The Wg signaling pathway promotes the formation of this complex by activation and maintenance of hth expression (Pichaud and Casares, 2000). Wg also activates otd expression in the early dorsal eye-antennal disc, which antagonizes Dpp induced compound eye primordium specification (Royet and Finkelstein, 1996). Egfr signaling increases the compound eye primordium induction activity of Eya by direct phosphorylation (Hsiao et al., 2001). Expression of the proneural transcription factor ato initiates the retinal differentiation state (Dokucu et al., 1996; Jarman et al., 1994, 1995). One of the downstream consequences of ato initiation is the activation of gl transcription in all compound eye primordium cells, which is essential for photoreceptor differentiation (Moses et al., 1989). Gl has been shown to directly activate its own transcription (Moses et al., 1989). The ato expressing R8 cells secrete Spi activating Egfr signaling, which is essential for survival

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1997). However, early retinal gene expression is not essential for the activation of ey expression during normal development (Bui et al., 2000). These data lead to a model in which the early retinal genes cooperate in building a positive feedback loop by re-enforcing ey and, secondarily, their own transcription (Fig. 3a) (Desplan, 1997). Consistent with the regulatory feedback model, physiologically functional SO binding sites have been demonstrated in an eye specific enhancer of the ey gene (Pauli et al., 2005). Based on in vitro evidence that Eya is able to bind So and Dac, the formation of a complex by these transcription factors is considered a central event during Drosophila CEY determination (Fig. 3a) (Chen et al., 1997; Pignoni et al., 1997). Deficiency mutations of eya and so are characterized by loss of all visual sense organs suggesting a universal requirement for Drosophila photo receptor sense organ development (Cheyette et al., 1994; Mardon et al., 1994; Zimmerman et al., 2000). Eya encodes a conserved transcription cofactor protein with protein tyrosine phosphatase activity (Bonini et al., 1993, 1997; Rayapureddi et al., 2003; Tootle et al., 2003). Its expression initiates slightly earlier than that of so and dac in the adult eye primordium (Kenyon et al., 2003). Epistasis analysis places eya above so and dac in the CEY gene determination network (Bui et al., 2000; Curtiss and Mlodzik, 2000; Halder et al., 1998). Importantly, eya is directly activated by Ey in collaboration with Dpp (Halder et al., 1998; Kenyon et al., 2003; Ostrin et al., 2006; Zimmerman et al., 2000). So is the Drosophila

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activation of the transcription factor encoding genes so, eyes absent (eya) and dachshund (dac) (Bonini et al., 1993, 1997; Cheyette et al., 1994; Hammond et al., 1998; Mardon et al., 1994; Rayapureddi et al., 2003; Serikaku and O’Tousa, 1994; Tavsanli et al., 2004; Tootle et al., 2003). Classified as early retinal genes (Desplan, 1997), eya, so and dac share a number of important characteristics: (I) their co-expression represents the first molecular manifestation of the CEY (Kenyon et al., 2003). (II) After initiation of differentiation, their coexpression persists in the front of the morphogenetic furrow. This early retinal gene co-expression domain constitutes to the ‘‘pre-proneural domain’’ (Fig. 1d), in which the EYD cells are prevented from initiating proneural gene expression by the expression of the helixeloopehelix transcription factor hairy (h) (Brown et al., 1995; Greenwood and Struhl, 1999). (III) Initiation of early retinal gene expression in the CEY depends on the presence of the transcription factors Ey and Tsh, and the activation of Decapentaplegic (Dpp) signaling (Fig. 3a) (Bessa and Casares, 2005; Chen et al., 1999; Halder et al., 1998). The early retinal genes are a crucial component of the CEY specification regulatory gene network (Fig. 3a). Demonstrating selector gene qualities, eya and dac induce ectopic eyes in misexpression essays (Bonini et al., 1997; Shen and Mardon, 1997). So enhances ectopic eye induction frequency if co-expressed with other RD genes (Pignoni et al., 1997). Ectopic eye induction by early retinal gene misexpression is associated with the activation of ey (Bonini et al., 1997; Shen and Mardon,

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and differentiation of adjacent compound eye primordium cells (Freeman, 1996; Tio et al., 1994). A second activating Egfr ligand expressed upon activation by Hh is vn (Amin et al., 1999). (b) Genetic interactions involved in specification and initial differentiation of the ocellus primordium. The genetic regulation of ocellus primordium development begins with the specification of the dorsal head cuticle compartment in the eye-antennal imaginal disc by expression of wg and hh (Royet and Finkelstein, 1996). The posterior margin of the eye-antennal imaginal disc implements the formation of compound eye primordium specification at the expense of dorsal cuticle fate by hh induced expression of dpp, which represses wg at the level of transcription (Royet and Finkelstein, 1997). In the dorsal head cuticle compartment, hh takes on a primordium promoting role by activating expression of vn, which stimulates Egfr signaling in the ocellar primordium (Amin et al., 1999). Egfr signaling activity is essential for normal ocellus development and has been shown to promote otd expression (Amin and Finkelstein, 2000). The mechanisms by which otd specifies ocellus primordium development in a concentration dependent manner are not known. Otd induces the homeobox segmentation gene engrailed (en) in the ocellus primordium (Royet and Finkelstein, 1996). En is sufficient to rescue ocellus development in otd loss of function situations (Royet and Finkelstein, 1996). However, while clonal deletion of en leads to deletion of the interocellar cuticle, it still allows for ocellus formation (Amin, 2003). The data demonstrate that the role of en is not ocellus primordium-specific despite the fact that it can compensate for otd. The determination of the ocellus primordial proper involves co-expression of eya and so (Cheyette et al., 1994; Zimmerman et al., 2000). Eya may be directly activated by Egfr as in the compound eye primordium (Hsiao et al., 2001). Ato and gl are essential for ocellus development and may be similarly regulated by Dpp and Wg signals as in the compound eye primordium. Reporter gene expression suggests the activation of optix by Ey in the ocellus primordial (Ostrin et al., 2006). The functional significance of this interaction during normal development is unknown. (c) The gene regulatory network leading to Bolwig organ primordium determination. As in the compound eye, Eya and So are likely to form a transcription factor complex that is critical for primordium determination. Both genes are essential for Bolwig organ development (Cheyette et al., 1994; Bonini et al., 1997). Dpp initiates eya and so expression (Chang et al., 2001). Unique for the embryonic visual system, high expression levels of Dpp activate zen which antagonizes eya and so expression by inducing apoptosis (Chang et al., 2001). Egfr antagonizes the effect of zen and functions as survival factor (Chang et al., 2003). Egfr signaling may also activate Eya by direct phosphorylation (Hsiao et al., 2001). The Hh signaling pathway is essential for the expression of ato and subsequently gl in the differentiating Bolwig organ primordium (Suzuki and Saigo, 2000). Spi activated Egfr signaling promotes Bolwig organ development as survival factor (Daniel et al., 1999). (d) Hypothesized ancient interactions in visual sense organ development based on the comparison of compound eye, ocellus and Bolwig organ specification gene networks. Co-expression of Eya and So, which form a visual sense organ fate instructing transcription factor complex, is followed by the induction of ato and gl. This core is present in the regulator gene networks of all Drosophila visual sense organs. The universal requirement of these gene activities is further supported by the loss of all visual sense organs in Drosophila deficient in any one of these genes (Cheyette et al., 1994; Jarman et al., 1995; Moses and Rubin, 1991; Zimmerman et al., 2000). Although the exact nature of the regulation between these genes is not known yet, the epistatic relationship of eya and so co-expression with respect to ato and subsequently gl activation is well established. Hh signaling is a conserved signal for ato activation. Pax-6 genes function as direct upstream activators of eya and so. The second essential signal required for so and eya activation comes from the Dpp signaling pathway. Wg signaling counteracts Dpp and is able to repress so and eya transcription. The antagonism between Dpp and Wg regulates position and timing of primordium formation. Conserved regulation of ato by Dpp and Wg in Drosophila chordotonal, compound eye photoreceptor and Johnston’s organ development suggests that the antagonistic interplay between Wg and Dpp signaling may coordinate the onset of ato expression in a similar manner (Niwa et al., 2004). Consistent effects of Wg and Dpp on ato during Bolwig organ and ocellus development are conceivable but yet untested. The data in compound eye and Bolwig organ development consistently point at a conserved role of Egfr signaling in induction of visual organ cell fates. It is further supported by the fact that Egfr signal activity is also indispensable for ocellus development. In the latter case, it still remains to be investigated if Egfr indeed operates at the level of final cell fate induction.

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2002). The Eya and So containing transcription factor complex must have therefore already been in use in the ancestor of Protostomia. In vertebrates, the situation is more complex due to the presence of multiple Six and Eya paralogs (for detailed review see Donner and Maas, 2004). Six-1 and Six-2, the closest orthologs of so, do not appear to be involved in eye development, although Six-2 is expressed in the developing retina (Kawakami et al., 1996; Laclef et al., 2003; Loosli et al., 1999). The suggestion has therefore been made that Six-3, the ortholog of optix, is the replacement of so in the vertebrate eye determination network (Donner and Maas, 2004). In support of this, Six-3 and Six-6 perturbations result in strong visual system phenotypes, there is a notable similarity in spatial regulation of Six-3 and so during eye field patterning, and Six-3 can bind Eya-1 (Hartenstein and Reh, 2002; Jean et al., 1999; Loosli et al., 1999; Purcell et al., 2005). However, as will be elaborated in a later section, an ancient status of optix in visual system development is not clearly supported in the Drosophila visual system. Further, Drosophila optix does not strongly bind to Eya unlike its vertebrate counterpart (Kenyon et al., 2005). Thus, although an interaction of Six and Eya proteins during eye determination appears evolutionarily ancient, these data also reinforce the impression of substantial differences between the vertebrate and invertebrate eye specification networks (Purcell et al., 2005).

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homolog of the vertebrate homeobox transcription factor gene Six-1 (Cheyette et al., 1994; Seimiya and Gehring, 2000; Serikaku and O’Tousa, 1994). The mechanism by which eya contributes to so activation is not known yet. Detailed analyses, however, document that this activation occurs in cooperation with toy and ey, the protein products of which have been shown to directly bind a visual system specific enhancer of so (Halder et al., 1998; Niimi et al., 1999; Punzo et al., 2002). Expression dynamics and regulatory aspects suggest correlated modes of action of so and eya during Drosophila visual sense organ development. In the CEY, so and eya are coexpressed together with dac in the pre-proneural domain and the morphogenetic furrow. Eya and so, however, continue to be expressed in the differentiating photoreceptor cells, whereas dac expression clears a few cell diameters posterior of the furrow (Mardon et al., 1994). These data imply that the function of eya and so reaches further into the photoreceptor differentiation than that of dac. Consistent with this, so has been found to directly activate transcription of the signaling molecule hedgehog (hh), the photoreceptor specific zinc finger gene glass ( gl ) and the runx type transcription factor lozenge (lz) in the differentiating retina (Pauli et al., 2005; Rogers et al., 2005; Yan et al., 2003). Strikingly consistent co-expression dynamics of eya and so have been reported for the developing BOL. Earliest expression of eya and so occurs in the embryonic visual anlage (Chang et al., 2001; Daniel et al., 1999; Halder et al., 1998). Paralleling the situation in the adult eye primordium, eya expression is activated slightly earlier (2 h after egg lay) than so expression (4 h after egg lay), providing circumstantial evidence for a similar epistatic relationship of eya over so as in the EAD (Bonini et al., 1998; Kumar and Moses, 2001c). During the dissociation of the visual anlage into separate organ primordia, eya and so continue to be expressed in the outer optic lobe anlagen and in the BOL, where co-expression persists in the differentiating photoreceptors (Cheyette et al., 1994; Daniel et al., 1999; Suzuki and Saigo, 2000). Co-expression of so and eya is also detected in the early OCE (Cheyette et al., 1994; Zimmerman et al., 2000). Once transcriptionally activated by toy (Punzo et al., 2002), so maintains its own expression in the OCE by a positive self-autoregulatory feedback loop (Fig. 3b) (Pauli et al., 2005). Less is known regarding the initiation of eya expression in the OCE. Interestingly, eya is expressed in the OCE of flies lacking so (Halder et al., 1998; Pauli et al., 2005). This is consistent with a position of eya upstream of so as in the CEY determination gene network. The possible dependence of so expression on eya still needs to be tested. In combination, the available evidence points to an ancient function of an early retinal gene transcription factor complex that incorporates Eya and So (Fig. 3d). Consistent with this, orthologs of both genes are involved in visual organ development in a wide variety of species. In Platynereis, the ortholog of Six-1/2 is expressed in all components of the larval and adult visual system (Arendt et al., 2002). Homologs of both eya and so have been found essential for platyhelminth eye regeneration (Mannini et al., 2004; Pineda et al., 2000; Salo et al.,

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3.4. The dachshund gene has no conserved role in Drosophila visual sense organ specification

The dac gene encodes conserved a DNA binding transcription cofactor, which is characterized by a putative DNA binding motif and a conserved Eya interaction domain (Hammond et al., 1998; Mardon et al., 1994; Tavsanli et al., 2004). In the CEY, dac expression is regulated by two enhancer elements (Chen et al., 1997; Pappu et al., 2005). A 50 located enhancer responds to ey, and is necessary for induction of dac transcription. The second enhancer integrates activation by so, eya and dpp (Pappu et al., 2005). These data indicate that the activation of dac transcription is a Pax-6 dependent event, whereas the maintenance of dac levels optimal for retinal patterning is Pax-6 independent and involves the other early retinal genes and Dpp. Dac can therefore be placed most downstream among the early retinal genes in the CEY network (Fig. 3a). The data on dac in the OCE argue against a universal requirement in Drosophila visual sense organ development. Dac is expressed in a wide area of the anterior EAD covering the OCE (Mardon et al., 1994). Nonetheless, ocellus development completes normally in dac null mutant Drosophila (Mardon et al., 1994). If dac is participating in BOL, development has not been specifically addressed. Despite the presence of so and eya, dac is not expressed in the early visual anlage (Kumar and Moses, 2001c). This may be explained by the lack of ey expression, which is the critical activator of dac expression in the EAD (Pappu et al., 2005). Expression of dac has been reported in the optic lobe anlagen of stage 9 embryos (Kumar and Moses, 2001c). The exact time point of dac expression onset, however, requires further analysis.

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parallel to the early retinal gene-dependent network (Fig. 3a) (Ostrin et al., 2006; Seimiya and Gehring, 2000). Little is known regarding potential roles of optix outside the CEY because of the lack of genetic mutants. Expression data suggest that optix is not active in the BOL, but possibly in the OCE (Seimiya and Gehring, 2000). This is further supported by OCE localized reporter gene expression from the optix regulatory element, which includes the Ey binding site (Ostrin et al., 2006). The dispensability of ey for ocellus development (Punzo et al., 2002), however, is not consistent with an essential role of optix dependent on ey in the OCE. Pending confirmation of optix expression and function in the OCE, optix may play an ancient role in visual sense organ specification. Considering the lack of optix expression in the embryo, this function needs to be assumed non-essential for the development of the rudimentary Bolwig organs as is the case for ey and toy (Seimiya and Gehring, 2000).

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The pre-proneural zone is followed by the onset of differentiation in the EAD (Fig. 1d). This transition is marked by the onset of transcriptional activation of the helixeloopehelix transcription factor atonal (ato) and the zinc finger transcription factor gene gl (Dokucu et al., 1996; Jarman et al., 1994; Jarman et al., 1995; Moses et al., 1989). As deficiency mutants of both genes are characterized by the loss of all visual sense organs (Daniel et al., 1999; Jarman et al., 1993, 1994; Moses et al., 1989), ato and gl need to be included in the discussion of Drosophila visual sense regulators of general importance. Expression of the proneural specification gene ato is the first indication of the beginning of differentiation in all three visual organ primordia. Close similarities in the dynamics and regulation of ato expression are to be noted in the developing CEY and BOL. First, ato expression is restricted in both organs to a short time window of early photoreceptor specification (Daniel et al., 1999; Suzuki and Saigo, 2000). Second, an initially wider expression of ato reduces to a smaller number of cells before being completely downregulated (Daniel et al., 1999; Jarman et al., 1993, 1994; Suzuki and Saigo, 2000). Third, in both primordia ato expression is dependent on Hh signaling activity (Fig. 3a and c) (Dominguez, 1999; Heberlein et al., 1995; Suzuki and Saigo, 2000). In the EAD, ato is also directly activated by Dpp through a neuron-specific enhancer element (Niwa et al., 2004). Whether the same enhancer element responds to Dpp in the BOL has not been investigated, but it seems to drive expression in the developing OCE, where ato is also strongly expressed (Fig. 3b) (Jarman et al., 1994; Niwa et al., 2004). It is not known if ato expression in the OCE preferentially persists in photoreceptor cells or is as transient as in the CEY and BOL. Like ato, gl expression initiates in all cells of the morphogenetic furrow. Unlike ato, gl expression refines to the photoreceptors posterior to the furrow and persists late into pupation (Ellis et al., 1993; Moses and Rubin, 1991). Whereas ato is specifically critical for the R8 specification step, gl is considered a master regulator of photoreceptor cell differentiation

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Transcriptional activation of dac in larval eye precursor cells seems possible at this stage considering the report of expression in the closely adjacent outer optic lobe anlagen (Kumar and Moses, 2001c). It is important to note that the invaginating optic lobe anlagen expresses toy, so and eya in addition to dac (Chang et al., 2001; Cheyette et al., 1994; Czerny et al., 1999; Kumar and Moses, 2001c). Since optic lobe anlagen cells have the capacity to transform into larval eye photoreceptors (see below) (Daniel et al., 1999; Schmucker et al., 1992), this data suggests that the transcriptional code specifying precursor cells of the larval and adult eyes is quite similar despite the substantial differences of its initial activation (compare Fig. 3a and c). Nonetheless, the limited information available precludes firm conclusions regarding a functional requirement of dac for Bolwig organ development at present. Considering the strong conservation of the Eya and So containing retinal determination complex, it is surprising that dac, which closely interacts with eya and so during CEY determination, is not required for OCE specification. Homologs of dac are very strongly expressed in the embryonic compound eye primordia of directly developing insects (Angelini and Kaufman, 2004; Inoue et al., 2004). However, RNAi mediated knockdown of dac in the milkweed bug Oncopeltus fasciatus does not result in noticable compound eye phenotypes (Angelini and Kaufman, 2004). Single and double knockout phenotypes of the dac homologous genes Dach-1 and Dach-2 of mouse exhibit no detectable consequences for eye development (Davis et al., 2001, 2006). These findings add further support to the conclusion that dac is not a universally essential component of visual organ development.

3.5. A parallel ey dependent CEY determination route: optix

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The Drosophila gene optix was identified by virtue of its sequence similarity to members of the vertebrate Six-3/6 gene family (Seimiya and Gehring, 2000; Toy et al., 1998). It is thus a paralog of the Six-1 orthology group member so. The DNA target sites of so and optix differ due to sequence divergence in the homeodomain region (Seimiya and Gehring, 2000; Toy et al., 1998). So and Optix proteins also contrast in cofactor affinity associated with amino acid differences in their Six protein interaction domains (Kenyon et al., 2005). Importantly, Optix fails to bind Eya unlike So (Kenyon et al., 2005). Consistent with this, co-expressing eya with so increases ectopic eye induction efficiency whereas co-expressing eya with optix does not (Seimiya and Gehring, 2000). The expression of optix in the EAD is more similar to that of ey and toy than of the early retinal genes. Optix expression is detected throughout the undifferentiated EYD but not in the differentiating retina posterior of the morphogenetic furrow (Seimiya and Gehring, 2000). Genome wide analysis identified optix as a direct target gene of Ey (Ostrin et al., 2006). The lack of ey expression in optix induced ectopic eye primordia leads to a model in which optix is part of a second induction cascade located downstream of ey that functions in

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4. Signaling pathways in Drosophila visual sense organ specification

striking aspect is the sequential induction of all compound eye retina cell fates except that of the R8 photoreceptor cell (Amin et al., 1999; Daniel et al., 1999; Freeman, 1996; Greenwood and Struhl, 1999; Spencer et al., 1998). Consistent observations have been made for the BOL (Daniel et al., 1999). Both organs employ Spitz (Spi) as the activating ligand (Fig. 3a and c). In the CEY, Spi is first secreted from R8 leading to Egfr signal activation in neighboring cells (Freeman, 1996; Tio et al., 1994). In the BOL, Spi secreted from the first four ato expressing photoreceptor cells is required for neural development and survival of the subsequently joining eight photoreceptor cells (Daniel et al., 1999). Unfortunately, it has not been investigated if Egfr signaling also plays a role in cell fate induction during ocellus differentiation. Finding the induction of photoreceptor, corneagenous and pigment cell fates depending on Egfr signaling similar to that of the various cell types in the compound eye would make an intriguing case for RTK signaling being an ancient patterning tool of visual sense organs. The data on the role of Egfr signaling during visual sense organ primordium specification is less conclusive. Based on misexpression experiments with wild type and constitutively active receptor forms, Egfr signaling has been suggested to suppress CEY in favor of antennal primordium fate at an early stage of EAD development (Kumar and Moses, 2001b). The finding, however, that Egfr signaling increases the eye specification efficiency of Eya by direct phosphorylation suggests an Egfr based biochemical mechanism for CEY induction (Hsiao et al., 2001). In the embryo, ectopic overactivation of Egfr signaling leads to spectacularly enlarged Bolwig organs connecting at the midline (Chang et al., 2003). This cyclopic eye phenotype, however, is not due to ectopic BOL specification but to cell death rescue in tissue biased to develop into Bolwig organ. Egfr antagonizes the cell death inducing effect of high Dpp signaling at the embryonic midline (see below) (Fig. 3c) (Chang et al., 2003; Dumstrei et al., 1998). In addition, Egfr signaling may enhance the activity of Eya expressed in the embryonic midline cells (Chang et al., 2003; Hsiao et al., 2001). These data thus point to a positive effect of Egfr on CEY and BOL specification. In the OCE, Egfr signaling is a critical parameter in early development. Reduction of Egfr signaling activity leads to reduced ocelli (Clifford and Schupbach, 1994). In this case, Vein (Vn) serves as the activating ligand of Egfr signaling (Amin et al., 1999). Vn is expressed in the tissue surrounding the ocellar cuticle field. Its transcriptional activation is triggered by Hh diffusing from the ocellar cuticle area into the interommatidial field periphery (Fig. 1f) (Amin and Finkelstein, 2000). Egfr signaling, in turn, has been found to activate otd in the OCE (Amin and Finkelstein, 2000). This effect constitutes Egfr as a primordium specifying signal upstream of otd in the OCE determination gene network (Fig. 3b). It is further possible, but remains to be tested, that Egfr signaling activates Eya, which is expressed in the OCE, by direct phosporylation in this context (Hsiao et al., 2001). Interestingly, Hh also activates vn transcription in the morphogenetic furrow, where vn is thought to be involved in the regulation of cell proliferation (Fig. 3a) (Amin et al., 1999; Daniel et al., 1999; Freeman,

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(Treisman and Rubin, 1996). Gl has been shown to affect the expression of a large number of genes in the CEY including early cell specification genes as well as later expressed genes such as rhodopsin (rh) (Treisman and Rubin, 1996). Interestingly, the same study identified a comparatively small number of gl dependent loci in the developing OCE or BOL (Treisman and Rubin, 1996). Gl expression in the developing BOL and OCE initiates similarly early as in the CEY (Moses and Rubin, 1991). In both cases, expression is photoreceptor-specific and persistent. Little is known with regards to how gl expression is initiated in the morphogenetic furrow. The maintenance of gl expression in photoreceptor cells, however, involves direct transcriptional auto-activation (Moses and Rubin, 1991). Expression and requirement of gl and ato in all Drosophila visual sense organs designate these genes as ancient regulators of photoreceptor development. This inference is backed by the essential involvement of the ato ortholog ath-5 in vertebrate retinal differentiation (Brown et al., 1998, 2001; Wang et al., 2001). Homologs of gl can be identified in diverse protostome and basal deuterostome species but not in vertebrates (Liu and Friedrich, unpublished). The role of gl in photoreceptor differentiation may be ancient but may have become lost during early vertebrate evolution. Studies on expression and function of gl in non-arthropod invertebrates will shed light on this issue.

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4.1. A controversial case: Notch

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The spatial coordination of selector gene expression in the EAD by signaling ligands is dynamic and complex, making it difficult to resolve the molecular genetic logic of signaling instructions that shape the Drosophila CEY. Notch (N) signaling has been proposed to induce eye primordium fate by activating ey (Kumar and Moses, 2001a; Kurata et al., 2000). Consistent with this view, N is essential for CEY formation and N signaling activity is detected along the midline of the early undifferentiated EYD (Cho and Choi, 1998; Dominguez and de Celis, 1998; Papayannopoulos et al., 1998). Recent work, however, shows that the expression of ey does not depend on N signaling activity. N is required for normal tissue proliferation through the activation of the eyegone gene (eye) (Dominguez et al., 2004; Kenyon et al., 2003). These findings point against a direct involvement of N in Drosophila CEY specification. An ancient function of N in visual primordium specification, which has been proposed based on the ectopic induction of Pax-6 expression and retinal development in zebrafish by N mis-activation (Onuma et al., 2002), has therefore to be considered with caution. 4.2. Epidermal growth factor receptor signaling: general role in cell fate but not primordium induction Receptor tyrosine kinase (RTK) signaling triggered by activation of the epidermal growth factor receptor (Egfr) participates in many aspects of CEY patterning. A particularly

M. Friedrich / Arthropod Structure & Development 35 (2006) 357e378

Dpp signaling exerts dose dependent effects on eya and so. Intermediate levels activate so and eya in the lateral head neuroectoderm, while maximal levels in the dorsal midline repress so and eya via activation of the homeodomain transcription factor zerknuellt (zen) (Fig. 3c) (Chang et al., 2001). The dorsal Dpp gradient in the blastoderm embryo thus shapes the visual anlage through concentration dependent activation and repression of the early retinal genes. The Dpp mediated induction of eya and so in the visual anlage is remarkable considering that ey, which is essential for the initiation of early retinal genes in response to Dpp signaling in the CEY, is not expressed in the visual anlagen cells (Kammermeier et al., 2001; Quiring et al., 1994). Moreover, so activation has been specifically shown to be independent of toy in the early visual anlage (Halder et al., 1998; Punzo et al., 2002). There is also evidence that the transcriptional activation of dac occurs independently of toy and ey in the embryonic head (Kurusu et al., 2000). In summary, these data reveal a conserved activation of the early retinal genes eya and so in the BOL and CEY by Dpp, which, however, is executed under diverged field selector gene requirements. Little is known regarding the relation of Wg and the early retinal genes in the embryonic head. Wg is expressed in a large area of the ocular segment neuroectoderm, the so-called ‘‘head blob’’ domain (Baker, 1988; Schmidt-Ott and Technau, 1992). Genetic lack-of-function analysis suggests that the main role of this domain resides in the production of wg expressing neuroblasts, which are essential for the development of the protocerebrum (Richter et al., 1998). The comparison with primitive insects shows that the Drosophila embryonic visual system is unusual in having been stripped of highly conserved ancestral expression domains (Liu et al., 2006). This data recommends the study of Wg signaling in the embryos of lesser derived species. In the flour beetle Tribolium castaneum, wg is expressed in polar domains in front of the developing larval eye primordium similar to the situation in the Drosophila EAD (see Liu et al., 2006). Conserved non-overlapping expression patterns of wg and the early retinal genes eya and so have been reported in the hemimetabolous grasshopper (Dong and Friedrich, 2005). It thus seems likely but remains to be confirmed that the Drosophila CEY paradigm of early retinal gene repression by Wg also holds for embryonic visual system development in insects. The role of Wg has been studied in more detail in the Drosophila OCE. In this case, Wg exerts time-dependent primordium promoting and repressive effects. In the second instar EAD, wg is expressed dorsally in overlap with otd (Royet and Finkelstein, 1997). Mis-activation experiments indicate that Wg is activating and maintaining otd expression in the early dorsal EYD (Fig. 3b) (Royet and Finkelstein, 1997). In this context, wg acts as a positive signal in the regional specification of the OCE. Consistent with the wg versus dpp antagonism paradigm, dpp represses dorsal EAD primordia fates in the posterior eye disc margin by pression of wg and otd (Fig. 3b) (Royet and Finkelstein, 1997). Wg changes its role as OCE agonist during EAD development in the third larval instar. At this point, wg expression

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1996; Spencer et al., 1998). The possibility thus exists that a regulatory loop involving Hh, Egfr and Vn regulates early patterning in both the CEY and the OCE. In summary, the combined data from the Drosophila visual system indicate an ancient role of RTK in the regulation of differentiation, and possibly primordium specification. In zebrafish, the progression of retinal ganglion cell differentiation is associated with a transient wave of RTK signalactivation (Neumann and Nuesslein-Volhard, 2000). The RTK activating signal during initiation and progression of differentiation are the fibroblast growth factors (Fgf) 8 and 3 (Martinez-Morales et al., 2005). Fgf ligands have also been identified as key to the progressive differentiation of the retina in chicken (McCabe et al., 1999). Although one has to account for the differences in activating ligands in different animal systems, an ancient involvement of RTK signaling is concievable (Hartenstein and Reh, 2002).

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The spatial and temporal onset of CEY determination and differentiation depends on the relative levels of the TGF-b signaling factor Dpp and the primordial Wnt family signaling factor Wg in the EAD (Kenyon et al., 2003; Niwa et al., 2004). As in other imaginal discs, Wg and Dpp signals exert antagonistic patterning roles in this context. This is reflected in the establishment of mutually exclusive expression patterns during the second half of EAD development (Bessa et al., 2002; Halder et al., 1995, 1998; Niwa et al., 2004; Shen and Mardon, 1997). The CEY fate promoting dpp is expressed in the posterior of the EAD and later in the morphogenetic furrow (Blackman et al., 1991; Treisman and Heberlein, 1998). Wg is restricted to strong polar domains in the anterior EYD in part due to Dpp repressing wg transcription in the posterior of the EAD (Chanut and Heberlein, 1997; Pignoni and Zipursky, 1997; Royet and Finkelstein, 1997; Wiersdorff et al., 1996). The antagonism of Wg and Dpp affects multiple levels of the CEY determination gene network (Fig. 3a). Most importantly in this context, dpp is necessary and sufficient to initiate retinal differentiation in the EAD which involves transcriptional activation of the early retinal genes eya, so and dac (Bessa and Casares, 2005; Burke and Basler, 1996; Chanut and Heberlein, 1997; Chen et al., 1999; Curtiss and Mlodzik, 2000; Dominguez and Hafen, 1997; Kenyon et al., 2003; Pignoni and Zipursky, 1997; Royet and Finkelstein, 1997; Wiersdorff et al., 1996). Wg, by contrast, represses retinal differentiation and early retinal gene expression (Baonza and Freeman, 2002; Lee and Treisman, 2001; Ma and Moses, 1995; Royet and Finkelstein, 1997; Treisman and Rubin, 1995). Striking similarities as well as differences concerning the role of Dpp and Wg can be noted in the embryonic visual system. Like in the EAD, Dpp is the essential signaling factor that activates so and eya expression in the visual anlage (Fig. 3c) (Chang et al., 2001). However, unlike in the EAD, embryonic

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4.3. Antagonistic regulation of eyes absent and sine oculis by Wingless and Decapentaplegic signaling

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a Dpp dependent regulatory element of ato in the OCE (Niwa et al., 2004). While it remains to be tested in detail if dpp has a similar role in ocellus development, the activation of eya and so by Dpp signaling during CEY and BOL development identifies this interaction as highly constrained. The data furthermore support an antagonistic role of Wg at least during OCE development. In summary, Wg and Dpp emerge as universal antagonistic regulators of so and eya expression in the Drosophila visual system (Fig. 3d). This situation is of striking resemblance to the control of eya and so homologs during visual system development in vertebrates. Repression of eye field selector genes by canonical Wnt signaling is a central theme in the vertebrate prosencephalon (Cavodeassi et al., 2005; Esteve and Bovolenta, 2006). In Xenopus, for instance, Wnt1 represses Six-1 and Eya-1 thereby delineating the posterior

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clears specifically from the OCE (Royet and Finkelstein, 1996). This downregulation appears to occur at the time when eya and so become upregulated in the OCE (Bessa et al., 2002; Royet and Finkelstein, 1996). This correlation suggests that Wg is a negative regulator of early retinal gene expression in both the CEY and OCE. Consistent with this, increasing Wg signaling strength during this time window reduces ocellus size (Royet and Finkelstein, 1996). A second mechanism responsible for this phenotype is repression of vn by Wg in the OCE periphery leading to reduction of Egfr signal activity in the OCE (Amin et al., 1999; Amin, 2003). Data on dpp at this stage of OCE development is not available. Published expression patterns speak against an activation of dpp transcription in the OCE (Rogers et al., 2005). Dpp ligand, however, may reach the OCE from the EYD margins. This is indicated by the activation of reporter gene expression from

Bolwig organ

Transcription factors Primordium specification twin of eyeless toy eyeless ey orthodenticle otd eyes absent eya

Pax-6 Pax-6 Otx Eya

Yes Yes Yes Yes

No No Yes Yes

Yes No Yes Yes

sine oculis

so

Six-1/2

Yes

Yes

Yes

dachshund optix eyegone homothorax

dac optix eyg hth

Dach Six-3/6 Meis

Yes Yes Yes Yes

? No No No

No ? ? ?

extradenticle

exd

Pbx

Yes

No

?

teashirt tailless engrailed zerknuellt

tsh tll en zen

Tsh Tlx En Hox-3

Yes ? Yes No

No Yes No Yes

? ? Yes No

Ath5 Kr-like factors -

Yes Yes No Yes

Yes Yes Yes Yes

Yes Yes No ?

Jarman et al., 1994 Moses et al., 1989; Moses and Rubin, 1991 Preiss et al., 1985; Schmucker et al., 1992 Goriely et al., 1999

Shh, Twhh

Yes

Yes

Yes

dpp

BMP-2, BMP-4

Yes

Yes

Yes

wg

Wnt-1

Yes

?

Yes

Notch Epidermal growth factor receptor

N Egfr

N Egfr

Yes Yes

? Yes

? Yes

spitz vein

Spi vn

TGF-a Neuroregulin family

Yes Yes

Yes ?

? Yes

Dominguez and Hafen, 1997; Heberlein et al., 1993; Ma et al., 1993; Mohler and Vani, 1992; Royet and Finkelstein, 1997 Heberlein et al., 1993; Royet and Finkelstein, 1997; Spencer et al., 1982 Ma and Moses, 1995; Rijsewijk et al., 1987; Treisman and Rubin, 1995 Artavanis-Tsakonas et al., 1983; Kidd et al., 1983 Baker and Rubin, 1989; Kumar et al., 1998; Livneh et al., 1985; Rodrigues et al., 2005; Wadsworth et al., 1985 Rutledge et al., 1992; Tio et al., 1994 Amin and Finkelstein, 2000; Schnepp et al., 1996; Spencer et al., 1998

Cell fate specification atonal ato glass gl Kruppel Kr Munster Mu

decapentaplegic wingless

Au

Signaling molecules hegdgehog hh

Ocellus

rs

on

Compound eye

th o

Abbreviation

r's

Vertebrate orthologs

pe

Drosophila gene

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Table 1 Genes regulating Drosophila visual sense organ development

References

Czerny et al., 1999 Daniel et al., 1999; Quiring et al., 1994 Chang et al., 2001; Finkelstein et al., 1990 Bonini et al., 1997; Daniel et al., 1999; Suzuki and Saigo, 2000 Cheyette et al., 1994; Daniel et al., 1999; Suzuki and Saigo, 2000 Kumar and Moses, 2001c; Mardon et al., 1994 Ostrin et al., 2006; Seimiya and Gehring, 2000 Jang et al., 2003; Jun et al., 1998 Bessa et al., 2002; Kurant et al., 1998; Rieckhof et al., 1997 Aspland and White, 1997; Bessa et al., 2002; Rauskolb et al., 1993 Bessa and Casares, 2005; Fasano et al., 1991 Daniel et al., 1999; Pignoni et al., 1990 Poole et al., 1985; Royet and Finkelstein, 1996 Chang et al., 2001; Chang et al., 2003; Doyle et al., 1986

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4.4. Positive control of visual sense organ determination by hedgehog The signaling molecule Hh is the third major global regulator of CEY patterning besides Dpp and Wg (Treisman and Heberlein, 1998). Like Dpp, Hh signaling is essential and sufficient to induce retinal differentiation in the EAD (Heberlein et al., 1995; Ma et al., 1993). Since Hh is also essential and sufficient for the induction of dpp, hh positions upstream of dpp in the CEY determination gene network (Fig. 3a) (Borod and Heberlein, 1998; Dominguez, 1999; Dominguez and Hafen, 1997; Lee et al., 2002; Royet and Finkelstein, 1997). The central event in the Hh signal transduction pathway is the inhibition of cleavage of the zinc finger transcription factor Cubitus interruptus (Ci). Full length Ci is a transcriptional transactivator (Ci155), but the truncated form (Ci75) represses transcription (Aza-Blanc et al., 1997). Hh pathway activation thus triggers a switch from repression to activation of Hh signaling target genes by Ci. Interestingly, the initiation of CEY differentiation occurs unhindered in tissue lacking ci, implying that the presence of activator Ci155 is not required (Kango-Singh et al., 2003; Pappu et al., 2003). This finding suggests that Hh controls initiation largely by mediating repression relief from Ci75, which classifies Hh as permissive signal in CEY determination. However, furrow progression in tissue deficient for components of the N and Dpp signaling pathways is sensitive to the presence of Ci155 implying subtle roles of Ci155 during normal development that are redundantly regulated by N and Dpp (Fu and Baker, 2003). The initiation of dpp and eya has been identified as a primary result of Ci75 repression release during CEY specification (Curtiss and Mlodzik, 2000; Pappu et al., 2003). Upon initiation of the morphogenetic furrow, Hh signaling is also required for activating the expression of proneural ato (Dominguez and Hafen, 1997). Upstream activating functions of Hh signaling can also be noted for BOL and OCE development. In the embryo, Hh is required for normal optic lobe, larval eye and EAD development (Chang et al., 2001; Suzuki and Saigo, 2000). Overactivation of Hh signaling leads to enlargement of all visual anlagen derivatives including a dorsally extended cyclopic Bolwig organ (Chang et al., 2001; Suzuki and Saigo, 2000). Unlike in the case of Egfr overactivation, which generates

a similar phenotype through repression of apoptosis, the Hh induced enlarged Bolwig organ is considered to reflect a capacity of Hh to induce specification and differentiation of larval eye precursor cells (Chang et al., 2001, 2003; Suzuki and Saigo, 2000). Consistent with this, manipulation of Patched (Ptc), a negative regulator of the Hh signaling, also suggests a link of Bolwig organ cell differentiation and Hh signaling (Schmucker et al., 1994). Ptc is specifically expressed in the optic lobe anlagen cells as opposed to the Bolwig organ cells (Chang et al., 2001). Decreasing Ptc levels increases the size of the larval eye by recruiting additional cells from the prospective optic lobe anlage (Schmucker et al., 1994). There are pronounced similarities and differences of Hh function during BOL and CEY development. Hh is involved in similar ways in the induction of differentiation in the CEY and BOL. In both primordia, Hh signaling is essential and sufficient to activate ato expression in the BOL (Chang et al., 2001; Dominguez and Hafen, 1997; Suzuki and Saigo, 2000). Further notable is the fact that the regulation of BOL specification by Hh is independent of activator Ci155, suggesting that Hh is a permissive signal in both the adult and larval eye (Suzuki and Saigo, 2000). The embryonic situation is, however, more complicated, since BOL development has been found also insensitive to repressor Ci75 levels (Suzuki and Saigo, 2000). Moreover the expression of dpp, eya and so is independent of hh in the embryonic visual system revealing considerable differences of hh related gene interactions between the CEY and BOL regulatory gene networks (Chang et al., 2001; Suzuki and Saigo, 2000). Several lines of evidence point to a role of Hh as a critical positive upstream signal in the OCE determination gene network (Fig. 3c) (Royet and Finkelstein, 1996; Thomas and Ingham, 2003). Hh expression is detected in the dorsal field of the EAD encompassing the OCE (Royet and Finkelstein, 1996). Increasing Hh signaling in the dorsal head region leads to the formation of ectopic ocellar structures, which is associated with expansion of otd expression via activation of Egfr (Amin and Finkelstein, 2000; Royet and Finkelstein, 1996). In contrast with the CEY and BOL specification paradigms, this aspect of Hh patterning is Ci-dependent (Amin and Finkelstein, 2000). These data assign Hh a role in the patterning of the dorsal head, which is essential for ocellus development. It has, however, not yet been investigated whether hh is expressed in the differentiating photoreceptor cells and whether hh has a specific effect on the initiation of photoreceptor development as in the CEY and BOL (Amin et al., 1999; Royet and Finkelstein, 1996). The significance of Hh or Ci on ato expression in the OCE also requires further investigation. Its consistently positive role in specification and differentiation of the Drosophila visual sense organs adds hh to the list of potentially ancient patterning signals in the development of photoreceptive organs (Fig. 3d). As in the case of the Wg and Dpp, informative similarities exist in vertebrates, where Hh signaling is involved at multiple levels of the visual system development. Extraretinal signaling from the prechordal plate is essential for the initiation of ath-5 in zebrafish (Stenkamp and Frey, 2003). In this case, Hh may activate optic stalk

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margin of the preplacodal ectoderm (Brugmann et al., 2004). The activation of Six-1 and Eya-1 in the early visual primordia, on the other hand, is dependent on BMP-4, a homolog of Dpp (Brugmann et al., 2004). Moreover, below threshold levels of BMP-4 lead to loss of Six-1 and Eya-1 expression, while above threshold levels of BMP-4 repress Six-1 and Eya-1 (Brugmann et al., 2004). This is similar to the dosage dependent regulation of eya and so by Dpp in the Drosophila visual anlage (Chang et al., 2001). A consistent body of evidence thus suggests that canonical Wnt signaling and BMP signaling are ancient antagonistic regulators of eya and so in the patterning of visual organ primordia.

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(v) Hh is a conserved upstream positive signal in visual sense organ differentiation. (vi) Direct activation of Eya and suppression of cell death may be ancient roles of Egfr signaling in visual sense organ specification. (vii) Egfr signaling may also be an ancient organizer of progressive cell differentiation in visual organ development. (viii) Ato is an ancient proneural regulator of photoreceptor specification. (ix) Gl is a potentially ancient photoreceptor specification and differentiation gene.

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This list should serve as a helpful guideline in the discussion of the evolutionary conservation of visual organ development in other animal groups. Indeed, for most of these aspects, similarities in non-arthropod species exist. Representing the first attempt to distill evolutionary information from all three Drosophila visual organs, this analysis is still of a preliminary nature. As further details of the genetic regulation of Drosophila visual organ development are becoming known, the list of shared mechanisms between larval eye, compound eye and ocellus development is likely to increase. Of particular importance will be more information on ocellus development which seems ‘‘under-investigated’’. Several groups have begun to apply the combination of complete genome sequence information, high throughput expression analysis, and bioinformatics tools to study the Drosophila CEY regulatory gene network (Jasper et al., 2002; Michaut et al., 2003; Ostrin et al., 2006). Although there is still a long way to go, a time point can be envisioned when the gene networks regulating the development of all Drosophila visual organs have been explored in detail (Chen and Mardon, 2005). It will be exciting to revisit these resources to gain ultimate insights into ancient mechanisms of visual organ determination from within the seven eyes of Drosophila.

5. Conclusions and perspectives

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expression of Fgf-8, which has been proposed to be the direct activator of retinal differentiation (Esteve and Bovolenta, 2006; Martinez-Morales et al., 2005). This scenario is reminiscent of the control of ocellus primordium development, where hh positively controls Egfr signaling by activating vn (Amin et al., 1999). In addition, vertebrate Hh signaling is considered to play a critical role in driving the progressive waves of differentiation in the retinal ganglion epithelium, retinal pigment epithelium and amacrine cell layer of the developing zebrafish eye (Neumann and Nuesslein-Volhard, 2000; Shkumatava et al., 2004; Stenkamp and Frey, 2003; Stenkamp et al., 2002; Stenkamp et al., 2000). The similarity to the Drosophila compound eye is particularly striking in the retinal ganglion cell layer of zebrafish, where ath-5 is transiently expressed in response to Hh signaling (Neumann and Nuesslein-Volhard, 2000). The same relationship is seen in the differentiating retina of the mouse (Masai et al., 2005). However, while Hh signaling enforces cell cycle exit and retinal ganglion differentiation in zebrafish, the same signal exerts a repressive effect on retinal ganglion cell differentiation in favor of activating retinal precursor cell division in the mouse (Masai et al., 2005; Neumann and Nuesslein-Volhard, 2000). The possibility is also discussed that the progressing induction of ath-5 expression in the zebrafish retina is independent of Hh signaling (Kay et al., 2005). Finally, amphibian Hh signaling does not interfere with neural patterning, but with the development of the retinal pigment epithelium (Perron et al., 2003). There is thus considerable variation in the ways Hh participates in vertebrate eye development. Nonetheless, its role as positive regulator during retinal induction and differentiation is as pervasive as in the Drosophila visual system, which may be taken as further evidence for a deep evolutionary rooting of Hh function in visual sense organ development.

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The comparison of the regulatory gene networks controlling compound eye, ocellus and Bolwig organ development is highly informative, revealing both intriguing commonalities as well as surprising differences. The intention of this investigation was to establish ancient aspects of the genetic regulation of visual organ development as shared features of the three organ formation processes. This rationale proved successful in identifying a number of likely ancient gene activities and interactions (Fig. 3d): (i) Pax-6 genes participate in the patterning of complex visual organs. (ii) Eya and So constitute an ancient transcription factor complex that holds a central position in visual sense organ determination gene networks. (iii) The expression of eya and so is activated by BMP signaling. (iv) Wg patterns visual organ primordia by repression of differentiation to maintain primordium growth.

Acknowledgements I am grateful to Ivanna Yavorenko for dedicated proofreading, Xiaoyun Yang and two anonymous reviewers for thorough and thoughtful comments. Support for this work came from NSF grant DBI-0091926 and a Career Development Chair Award by Wayne State University.

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Brown, N.L., Sattler, C.A., Paddock, S.W., Carroll, S.B., 1995. Hairy and emc negatively regulate morphogenetic furrow progression in the Drosophila eye. Cell 80, 879e887. Browne, W.E., Schmid, B.G., Wimmer, E.A., Martindale, M.Q., 2006. Expression of otd orthologs in the amphipod crustacean, Parhyale hawaiensis. Dev. Genes Evol. 216, 581e595. Brugmann, S.A., Pandur, P.D., Kenyon, K.L., Pignoni, F., Moody, S.A., 2004. Six1 promotes a placodal fate within the lateral neurogenic ectoderm by functioning as both a transcriptional activator and repressor. Development 131, 5871e5881. Bui, Q.T., Zimmerman, J.E., Liu, H., Bonini, N.M., 2000. Molecular analysis of Drosophila eyes absent mutants reveals features of the conserved Eya domain. Genetics 155, 709e720. Burke, R., Basler, K., 1996. Hedgehog-dependent patterning in the Drosophila eye can occur in the absence of Dpp signaling. Dev. Biol. 179, 360e368. Callaerts, P., Clements, J., Francis, C., Hens, K., 2006. Pax6 and eye development in Arthropoda. Arthropod Structure & Development 35, 379e391. Callaerts, P., Munoz-Marmol, A.M., Glardon, S., Castillo, E., Sun, H., Li, W.H., Gehring, W.J., Salo, E., 1999. Isolation and expression of a Pax-6 gene in the regenerating and intact planarian Dugesia tigrina. Proc. Natl. Acad. Sci. USA 96, 558e563. Casares, F., Mann, R.S., 1998. Control of antennal versus leg development in Drosophila. Nature 392, 723e726. Cavodeassi, F., Carreira-Barbosa, F., Young, R.M., Concha, M.L., Allende, M.L., Houart, C., Tada, M., Wilson, S.W., 2005. Early stages of zebrafish eye formation require the coordinated activity of Wnt11, Fz5, and the Wnt/beta-catenin pathway. Neuron 47, 43e56. Chang, T., Mazotta, J., Dumstrei, K., Dumitrescu, A., Hartenstein, V., 2001. Dpp and Hh signaling in the Drosophila embryonic eye field. Development 128, 4691e4704. Chang, T., Shy, D., Hartenstein, V., 2003. Antagonistic relationship between Dpp and EGFR signaling in Drosophila head patterning. Dev. Biol. 263, 103e113. Chanut, F., Heberlein, U., 1997. Role of decapentaplegic in initiation and progression of the morphogenetic furrow in the developing Drosophila retina. Development 124, 559e567. Chen, R., Amoui, M., Zhang, Z., Mardon, G., 1997. Dachshund and eyes absent proteins form a complex and function synergistically to induce ectopic eye development in Drosophila. Cell 91, 893e903. Chen, R., Halder, G., Zhang, Z., Mardon, G., 1999. Signaling by the TGF-beta homolog decapentaplegic functions reiteratively within the network of genes controlling retinal cell fate determination in Drosophila. Development 126, 935e943. Chen, R., Mardon, G., 2005. Keeping an eye on the fly genome. Dev. Biol. 282, 285e293. Cheyette, B.N., Green, P.J., Martin, K., Garren, H., Hartenstein, V., Zipursky, S.L., 1994. The Drosophila sine oculis locus encodes a homeodomain-containing protein required for the development of the entire visual system. Neuron 12, 977e996. Cho, K.O., Chern, J., Izaddoost, S., Choi, K.W., 2000. Novel signaling from the peripodial membrane is essential for eye disc patterning in Drosophila. Cell 103, 331e342. Cho, K.O., Choi, K.W., 1998. Fringe is essential for mirror symmetry and morphogenesis in the Drosophila eye. Nature 396, 272e276. Clifford, R., Schupbach, T., 1994. Molecular analysis of the Drosophila EGF receptor homolog reveals that several genetically defined classes of alleles cluster in subdomains of the receptor protein. Genetics 137, 531e550. Cohen, S.M., Jurgens, G., 1990. Mediation of Drosophila head development by gap-like segmentation genes. Nature 346, 482e485. Curtiss, J., Halder, G., Mlodzik, M., 2002. Selector and signalling molecules cooperate in organ patterning. Nat. Cell Biol. 4, E48eE51. Curtiss, J., Mlodzik, M., 2000. Morphogenetic furrow initiation and progression during eye development in Drosophila: the roles of decapentaplegic, hedgehog and eyes absent. Development 127, 1325e1336. Czerny, T., Halder, G., Kloter, U., Souabni, A., Gehring, W.J., Busslinger, M., 1999. Twin of eyeless, a second Pax-6 gene of Drosophila, acts upstream of eyeless in the control of eye development. Mol. Cell 3, 297e307.

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