Human Molecular Genetics, 2000, Vol. 9, No. 6 917-925
© 2000 Oxford University Press
Vertebrate eye development as modeled in Drosophila
Graduate Program in Biological and Biomedical Sciences, Harvard Medical School and Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
Received 7 January 2000; Accepted 19 January 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONVERTEBRATE EYE DEVELOPMENT AND...Pax6 IN THE FLY:...FROM FLY TO MOUSEEXTENDING THE ANALOGY: THE...CONCLUSIONS: A SIMPLE ANALOGY...REFERENCES |
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Pax6, a member of the paired-box family of transcription factors, is critical for oculogenesis in both vertebrates and insects. Identification of potential vertebrate Pax6 targets has been guided by studies in Drosophila, where the Pax6 homologs eyeless (ey) and twin of eyeless (toy) function within a network of genes that synergistically pattern the developing fly eye. These targets, which share homology with the fly genes sine oculis, eyes absent and dachshund, exist in mice and humans as the Six, Eya and Dach gene families. Members of these gene families are present in the developing vertebrate eye, and preliminary studies suggest that they may function in a network analogous to that in the fly. Thus, despite radically different architecture, a similar molecular scaffold underlies both vertebrate and fly eye patterning, suggesting that the considerable power of Drosophila genetics can be harnessed to study mammalian ocular development.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONVERTEBRATE EYE DEVELOPMENT AND...Pax6 IN THE FLY:...FROM FLY TO MOUSEEXTENDING THE ANALOGY: THE...CONCLUSIONS: A SIMPLE ANALOGY...REFERENCES |
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In recent years, genetic analysis has revealed that numerous regulatory proteins are conserved across metazoan phyla. While predictable for genes controlling basic cellular functions, the conservation of genes involved in the establishment of the body plan was unexpected. Still more surprising is the emerging realization that the genetic relationships between individual genes are also conserved, so that similar genetic cascades pattern analogous anatomical structures in evolutionarily distant organisms.
Studies of the transcription factor Pax6 provide a striking illustration of how such genetic conservation can impact the understanding of vertebrate development. Here we show how examination of the Pax6 gene cascade in Drosophila has shed light not only on this regulatory hierarchy but also on other prototypical regulators of vertebrate eye formation. First, we review the role that Pax6 plays in vertebrate eye development and disease. Second, we discuss studies of two Drosophila Pax6 homologs, eyeless (ey) and twin of eyeless (toy), which inform analysis of the vertebrate Pax6 pathway. Finally, we discuss several homologs of additional Drosophila eye patterning genes and their potential roles in vertebrate oculogenesis. The theme emerging from these studies is that not only Pax6, but the entire Pax6 genetic cascade, has been conserved in the evolution of eye development. This suggests that, despite a radically different optic architecture, the fly eye provides a powerful genetic model for the analysis of vertebrate eye development.
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VERTEBRATE EYE DEVELOPMENT AND THE ROLE OF Pax6 |
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TOPABSTRACTINTRODUCTIONVERTEBRATE EYE DEVELOPMENT AND...Pax6 IN THE FLY:...FROM FLY TO MOUSEEXTENDING THE ANALOGY: THE...CONCLUSIONS: A SIMPLE ANALOGY...REFERENCES |
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Morphological development of the vertebrate eye begins with the formation of an outpouching of the diencephalon called the optic vesicle (Fig. 1A). The optic vesicle subsequently contacts the head ectoderm (Fig. 1B) and signals the induction of a pseudostratified thickening of the ectoderm called the lens placode (Fig. 1C). The lens placode invaginates and separates from the surrounding ectoderm to form a lens vesicle (Fig. 1D and E). Eventually, the cells of the lens vesicle differentiate into fiber cells characteristic of the adult lens (Fig. 1F). Concomitantly, the optic vesicle folds inward on itself, surrounding the lens vesicle and forming the optic cup (Fig. 1D and E), which will eventually comprise the neural and pigmented layers of the adult retina (Fig. 1F) (1).
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Although the early stages of vertebrate eye development have been the subject of numerous embryological experiments (reviewed in ref. 2), until recently little was known about the molecular identities of the regulators involved. Pax6, a member of the vertebrate Paired box family of transcription factors provided an exception to this, as its expression pattern initially suggested a role in eye development (3). Prior to lens induction, Pax6 is expressed in a broad domain of head ectoderm and in the optic vesicle (Fig. 2A and B), and expression becomes restricted to the lens placode, lens vesicle and optic vesicle as development proceeds (Fig. 2C and D) (4). Restriction of Pax6 to lens placode ectoderm occurs prior to ectodermal thickening (Fig. 2C), suggesting that Pax6 expression in the ectoderm is regulated in response to inductive signals from the optic vesicle.
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Mutations in human and mouse confirm that Pax6 plays a critical role in eye formation. Haploinsufficiency for PAX6 in humans causes aniridia, a heritable panocular disorder characterized by iris and foveal hypoplasia, often accompanied by cataracts, corneal opacification and progressive glaucoma (5,6). Homozygous PAX6 mutations result in anophthalmia, nasal hypoplasia and central nervous system defects (7). Mutations in mouse Pax6 cause the Small eye (Sey) mutation (8). Like aniridia, Sey is inherited in a semi-dominant fashion, with Sey/+ heterozygotes exhibiting corneal and lenticular abnormalities and Sey/Sey homozygotes lacking eyes entirely (9). The close similarities in phenotype and mode of inheritance between aniridia and Sey suggest that Pax6 functions equivalently in the regulation of both mouse and human ocular development.
The failure of homozygous Pax6 mutants to form a lens placode indicates an early role for Pax6 in eye development. Tissue recombination experiments confirm this, as lens formation requires functional Pax6 in both the optic vesicle and the head ectoderm (10,11; J. Enwright and R. Grainger, personal communication). Chimera studies also indicate a cell autonomous role for Pax6 in the developing retina (12). Furthermore, injection of Pax6 RNA into Xenopus embryos is capable of producing both ectopic retinal and lentoid structures, though the frequency of retinal formation is low (13,14). These results suggest that Pax6 is critical for early development of both the lens and the retina.
Studies of Pax6 mutations have offered insight into Pax6 function and regulation (reviewed in refs 15,16; see also http://hgu.mrc.ac.uk/Softdata/PAX6/ for a summary of human PAX6 mutations). However, evolutionary conservation has also played an important part in illuminating the larger context in which Pax6 acts. Pax6 homologs are required for eye or light-sensing structure development across a wide range of species (5,13,17–24). Analyses of Pax6 homologs in the fruit fly Drosophila have identified genes cooperating with Pax6 in patterning the fly eye. Guided by these studies, several vertebrate gene families have been discovered with homology to fly optic patterning genes and expression in the vertebrate eye.
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Pax6 IN THE FLY: MASTER REGULATOR OR NETWORK MANAGER? |
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TOPABSTRACTINTRODUCTIONVERTEBRATE EYE DEVELOPMENT AND...Pax6 IN THE FLY:...FROM FLY TO MOUSEEXTENDING THE ANALOGY: THE...CONCLUSIONS: A SIMPLE ANALOGY...REFERENCES |
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Despite their common requirement for Pax6, vertebrate and insect eyes are markedly different. The Drosophila compound eye is made up of ~750 repeated crystalline units called ommatidia, each containing a precisely arranged pattern of eight photoreceptors and a set of non-neural support cells (reviewed in ref. 25). During the third instar of larval development, columns of cells are induced to differentiate along the posterior margin of the eye imaginal disc (Fig. 1G). The first cell recruited into each nascent ommatidium becomes the R8 photoreceptor cell, and subsequently induces surrounding cells to join the growing cluster. As cells immediately anterior to the furrow are induced by their more mature neighbors to join ommatidial clusters, a wave of differentiation known as the morphogenetic furrow moves from posterior to anterior across the eye disc.
Because the fly eye is morphologically distinct from that in vertebrates, it has been surprising to learn that two homologs of vertebrate Pax6, ey and toy, function in Drosophila eye development (20,26). The fly Pax6 homolog ey is expressed in the eye anlagen as early as these structures can be detected, with expression during subsequent larval stages becoming restricted to cells anterior to the morphogenetic furrow (20). ey is clearly a key factor in optic patterning, as mutation of ey disrupts eye formation. In addition, ectopic expression of ey in wing, antennal and leg imaginal discs induces the formation of ectopic eyes in these structures (27), leading to the suggestion that ey functions as a ‘master regulator’ of eye development. However, a master regulator gene for the eye might be expected to impose eye identity on any cell in which it is expressed. This is not the case for ey, as expression is detected in non-optic tissues (20). Furthermore, ey null mutations are lethal (28), suggesting that ey has functions auxiliary to eye development. Thus, ey must act in concert with other factors to specify optic fate.
The idea of ey as a master regulator is also complicated by the presence in Drosophila of a second Pax6 homolog that is expressed even earlier in development than ey (26). This gene, toy, is more likely to be orthologous to vertebrate Pax6 than ey, as the C-terminal transcription activation domain is more closely related. Ectopic toy expression induces ectopic ey, consequently driving ectopic eye formation (26). Several toy binding sites which are essential for eye-specific expression have been identified in an ey enhancer (26,29), suggesting ey regulation by toy. However, as toy is also expressed in non-optic tissues, the presence of toy alone cannot fully explain the regulation of fly eye development.
Recent work demonstrates that the induction of ectopic eyes by ey occurs only at sites of coexpression with decapentaplegic (dpp), a member of the TGF-ß family of growth factors (30,31). In addition, coexpression of ectopic dpp and ey markedly expands the domains in which ectopic eyes will form (31). ey and dpp do not appear to regulate each other, suggesting that ey and dpp act synergistically to induce optic fate.
In addition to ey and dpp, several other genes are capable of inducing ectopic eyes when misexpressed. Mutations in three of these genes, sine oculis (so), eyes absent (eya) and dachshund (dac), lead to defects in eye development (32–34). eya and dac are weakly capable of imposing an eye fate on non-ocular tissue (35,36) and, like ey, this ectopic eye induction is enhanced by ectopic coexpression with dpp (31). Furthermore, when eya and dac or so are expressed together, a much more dramatic induction of ectopic eyes is observed, a likely consequence of the protein–protein interactions which are observed between Eya and either So or Dac (37,38).
Epistasis analyses indicate that toy, ey and dpp act upstream of so, eya and dac (31,35,38,39) and, in the case of so, the Ey protein directly regulates transcription through an eye-specific enhancer (40). dac acts downstream of both eya and so, which regulate each other’s expression (37–39). However, the induction of ectopic eyes by eya, so and dac induces ey expression and requires ey function, but does not induce toy expression (35–39). Furthermore, functional Eya protein is required to maintain expression of dpp in the eye imaginal disc (41). These results suggest the genetic model outlined in Figure 3A, where a complex network of genes serves to coordinate early eye induction in the fly.
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FROM FLY TO MOUSE |
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TOPABSTRACTINTRODUCTIONVERTEBRATE EYE DEVELOPMENT AND...Pax6 IN THE FLY:...FROM FLY TO MOUSEEXTENDING THE ANALOGY: THE...CONCLUSIONS: A SIMPLE ANALOGY...REFERENCES |
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The evolutionary conservation of Pax6 suggests the presence of common functional mechanisms controlling oculogenesis. In support of this hypothesis, Drosophila and mouse Pax6 are equally capable of inducing ectopic eyes in fly imaginal discs (27) and a Drosophila eye-enhancer region from ey accurately reproduces features of endogenous Pax6 expression in mice (42). Given this apparent functional conservation, one approach to identifying Pax6 target genes has been to extrapolate from the Drosophila eye-forming hierarchy. Based on this strategy, mammalian homologs of dac, eya and so have been cloned, and examination of their roles in vertebrate development has begun.
The eya homologs
Four eya homologs have been cloned in the mouse. Eya1 is weakly expressed in the lens placode and Eya1, -2 and -4 are expressed in the nasal placode (43–45). Both of these structures are affected in Sey/Sey mice. Furthermore, expression of both Eya1 and -2 is downregulated in the absence of functional Pax6 in the lens and nasal ectoderm suggesting that, as in the fly, Eya lies downstream of Pax6 in a genetic pathway (43).
Analysis of the vertebrate Eya gene products reveals two distinct domains. The Eya domain is a highly conserved 271 amino acid region at the C-terminus of the protein (43). In the fly, the Eya domain is the site of protein–protein interactions between Eya and So or Dac (37,38). The conservation of this domain suggests that such interactions occur in vertebrates, a conclusion supported by in vitro experiments (46,47). At the N-terminus of each of the Eya genes is a non-conserved proline-, serine-, threonine-rich (PST) region capable of functioning as a transcriptional activator (48). However, neither the Eya nor the PST domains binds DNA (P. Xu and R. Maas, unpublished data), suggesting that Eya family members act in concert with other DNA binding proteins to regulate transcription.
Vertebrate eya homologs have also been identified in humans, where haploinsufficiency for EYA1 is responsible for branchio-oto-renal (BOR) syndrome (49,50). Although neither BOR syndrome nor the mouse Eya1 knockout includes major optic abnormalities as a common feature, a subset of human EYA1 mutations results in cataracts and anterior segment defects (51,52). Nevertheless, the role of Eya genes in vertebrate eye development remains unclear.
The so-related genes Six3 and Optx2
In the mouse, the Six gene family consists of six homologs of Drosophila so (53–59). Like fly so, all of these genes contain a homeodomain and a 110 amino acid region immediately 5' of the homeodomain called the Six domain. Several Six family members are expressed in the developing retina, and Six3 is also expressed in the invaginating lens vesicle (54,60). Consistent with the epistasis between so and ey in flies, Six3 expression is absent from the presumptive lens ectoderm of Sey/Sey embryos (S. Wawersik and P. Purcell, unpublished data). In the teleost fish medaka, ectopic expression of mouse Six3 leads to the development of ectopic lens and retina (61,62), whereas mutations in the human SIX3 gene lead to holoprosencephaly and microphthalmia (63). These data argue for functional importance of vertebrate Six3 in eye formation.
Though expressed in the developing eye, Six3 is not the most closely related Six family member to Drosophila so. Recently, Optx2, another member of the Six gene family, was cloned in chick and mouse (57–59,64). However, whereas Optx2 (also referred to as Six6 or Six9) is expressed in the optic vesicle, no expression is found in the developing lens placode. A second so-related gene has also been identified in Drosophila that appears to be the true ortholog of both Six3 and Optx2 (64). This gene, named optix, is closely linked to so, and may represent a gene duplication. However, as no fly eye mutants map near the optix locus, the function of this gene in insect eye formation is currently unknown.
Vertebrate Optx2 appears to be important in eye development, as human chromosomal deletions of the OPTX2-containing region lead to bilateral anophthalmia (65). Misexpression of Optx2 in retinal pigment epithelium primary cultures induces expression of neural retina-specific markers, and overexpression of Optx2 in Xenopus eyes increases the proliferation of retinal cells (64,66). These results suggest that the role for Optx2 lies in neural retina development.
Dach1 and -2, homologs of Drosophila dac
Two homologs of Drosophila dac have been cloned, each containing two similar domains of high conservation with dac, referred to as Dachbox-N and -C (47,67–70). The role of the Dachboxes is unknown, though they are weakly homologous with Ski and Sno, which negatively regulate TGF-ß signal transduction (71–73).
The role of Dach1 in mammalian development is also unclear, though its expression suggests a possible function in early retinal development (67–70). Despite the presence of dac homologs in the vertebrate eye, no Dach mutations have yet been described in mouse or human, so it is unclear whether vertebrate Dach plays a role in optic patterning analogous to that in flies. However, the recent identification of a second dac homolog, Dach2, suggests conservation of the genetic hierarchy seen in Drosophila (47). Chicken Dach2 interacts with members of the vertebrate Pax, Six and Eya families to regulate myogenesis, suggesting the use of a conserved genetic cassette in the patterning of multiple vertebrate structures.
Analysis of bone morphogenetic protein (BMP) mutations
In addition to homologs of the downstream targets of ey, recent analyses of BMPs also reveal a role for these growth factors in optic patterning. Gain-of-function experiments in chick suggest that Bmp4, a vertebrate homolog of dpp, functions in dorsoventral patterning of the optic vesicle (74). Null mutants in either the Bmp4 or the Bmp7 gene, the latter a homolog of the fly dpp modifier 60A, both fail to form lens placodes (75–77). Moreover, epistasis analyses suggest that, like dpp in the fly, Bmp4 and -7 each cooperate with Pax6 in regulating eye formation, apparently serving to maintain lens placode development after its induction. Bmp7 is also required to maintain expression of Six3 and Optx2 in the optic vesicle, and Bmp7 mutant optic vesicles appear to be incapable of supporting lens development in wild-type ectoderm (S. Wawersik, unpublished data).
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EXTENDING THE ANALOGY: THE FLY AS A MODEL FOR HUMAN OCULOGENESIS AND DISEASE |
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TOPABSTRACTINTRODUCTIONVERTEBRATE EYE DEVELOPMENT AND...Pax6 IN THE FLY:...FROM FLY TO MOUSEEXTENDING THE ANALOGY: THE...CONCLUSIONS: A SIMPLE ANALOGY...REFERENCES |
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Despite some differences, the apparent conservation of elements of the Pax6 genetic cascade suggests that homologs of additional Drosophila eye patterning genes are also conserved in vertebrates. Indeed, the vertebrate genes Otx1, Otx2 and Crx share homology with Drosophila orthodenticle (otd), a homeobox transcription factor necessary for fly head and photoreceptor development (78–83). Mouse mutations in Otx2 lead to abnormalities in eye, ear and brain development (84), and Crx-deficient mice exhibit defects in photoreceptor cell development (85). Though no mutations have been reported in either of the human OTX genes, mutations in the human CRX gene are associated with cone–rod dystrophy-2, retinitis pigmentosa and Leber congenital amaurosis (82, 86,87). Given that the mouse and human Otx genes can rescue otd mutations in Drosophila, and otd cDNA can rescue mouse Otx1 deficiency (88,89), it seems likely that, as with the Pax6 pathway, analysis of the vertebrate Otx and Crx genetic cascades can benefit from genetic studies in the fly.
One of the most common congenital brain anomalies in humans is holoprosencephaly (HPE), affecting ~1 in 16 000 live births and 1 in 250 embryos. In addition to microphthalmia, mutations in the human SIX3 gene lead to HPE (63), suggesting that the two phenotypes may be related. Interestingly, the first gene known to cause human HPE, Sonic Hedgehog, also has a fly homolog that is critical for eye development (90,91). It is therefore possible that a genetic cascade similar to that elucidated in the fly eye also underlies human HPE.
In addition to Pax6, other Pax genes are also involved in oculogenesis, as Pax2 patterns the optic stalk (92). The fly eye mutant sparkling is due to mutations in a Pax2 Drosophila homolog (93), suggesting parallels in the insect and vertebrate roles of Pax2. Negative regulation of Pax2 in the optic stalk by the dpp homolog Bmp4 and by Tbx5, a homolog of the Drosophila optimotor blind gene, further highlights these parallels (74). In addition to patterning the optic stalk, both human and mouse Pax2 mutations lead to kidney and ear defects (94,95). Ear and kidney abnormalities are also seen in EYA1 haploinsufficient BOR patients and in mouse Eya1 mutations (49–51), suggesting that, as in myogenesis, the insect eyeless genetic cascade has been redeployed in vertebrate ear and kidney patterning.
A number of additional vertebrate genes with roles in eye development have Drosophila homologs. Prox1, a homolog of the fly eye patterning gene prospero, is essential for lens fiber elongation in the mouse (96,97) and mutations in a human homolog of the Drosophila crumbs gene cause retinitis pigmentosa (98). The Rx/rax homeobox gene, a potential regulator of Pax6, is required for early optic vesicle and neural patterning in mice (99). Similarly, expression of the fly homolog of Rx, DRx, is detected in the developing head (100), suggesting a role in brain and eye development.
Finally, two genes regulated by Pax6 in the vertebrate optic cup are Math5 and Hes1, which are murine homologs of Drosophila atonal and hairy (101). Interestingly, hairy is a target of dpp in the regulation of morphogenetic furrow progression (91), suggesting a potential interaction with ey/dpp in eye patterning. Although the relationship of these genes to the Pax6 pathway is still unclear, their presence further underlines the striking parallels between the molecular control of vertebrate and insect eye patterning.
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CONCLUSIONS: A SIMPLE ANALOGY FROM THE COMPOUND EYE |
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TOPABSTRACTINTRODUCTIONVERTEBRATE EYE DEVELOPMENT AND...Pax6 IN THE FLY:...FROM FLY TO MOUSEEXTENDING THE ANALOGY: THE...CONCLUSIONS: A SIMPLE ANALOGY...REFERENCES |
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In recent years, identification of the common role played by Pax6 in flies and vertebrates has furthered understanding of the molecular regulation of oculogenesis. These studies have sparked the surprising realization that regulators of eye development are conserved across large evolutionary distances. As a result, vertebrate homologs of eya, so and dac have been cloned, and their expression patterns and conserved functional domains suggest that, like Pax6, they may also have important roles in vertebrate eye formation. Further supporting this hypothesis are loss- and gain-of-function experiments, summarized in Table 1. Preliminary epistasis analysis suggests that regulatory relationships are also preserved between these genes (43,47,76,77). Thus, rather than simply conserving the use of individual elements in eye developmental regulation, it appears that evolution has maintained the use of an entire genetic cassette (Fig. 3B).
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However, even as vertebrate constituents of the Pax6-dependent genetic cascade are being identified, several critical questions remain. Among these is why vertebrate homologs of eya, so and dac are found as members of gene families. As the eye is one of several vertebrate sensory organs developing through placodal invagination, one possibility is that members of these families have become specialized to pattern other organs. Mutations in Eya and Six family members lead to defects in other craniofacial structures and the kidney, suggesting the use of a conserved cassette in patterning of multiple organs (49–51,63,65). The demonstration that Pax3, Eya2, Six1 and Dach2 function synergistically in myogenesis further supports the cassette hypothesis, implying incorporation of the eye patterning cassette into muscle development (47).
The existence of multiple members of the Eya, Six and Dach gene families in vertebrates also raises questions about the role of protein–protein interactions in their biological function. In addition to cassette conservation in myogenesis, members of the Six gene family induce nuclear translocation of Eya proteins in COS7 cells, further confirming that the synergistic action of so and eya is preserved in vertebrates (46). Moreover, in these experiments, Eya family members interact preferentially with different subsets of Six proteins, suggesting that, in vivo, each of these combinations has a distinct functional outcome. It is important to note that at present none of the Eya proteins has been shown to be translocated by Six3, the only Six family member known to be expressed in the lens placode, suggesting the involvement of currently unidentified members of the Eya family in lens patterning. Alternatively, this result might indicate a distinction between fly and vertebrate optic specification, where vertebrate eye pattern is established in the absence of an Eya family member.
A second important difference between flies and vertebrates is the presence of toy in Drosophila. With the exception of zebrafish, which is likely to have undergone several genome-wide duplications during evolution (102), careful attempts to find a second Pax6 gene in vertebrates have proven unsuccessful (M. Busslinger, personal communication). As ey and toy map near each other in the Drosophila genome, the existence of two fly Pax6 genes may thus be the result of a gene duplication (26). Alternatively, as vertebrate Pax6 regulates its own expression in the eye (4,103), it is possible that the positive regulatory function of toy in the fly has been subsumed by the autoregulatory capacity of Pax6 in vertebrates.
As further parallels between Drosophila and vertebrates are uncovered (Table 2), the challenge will be to elucidate the vertebrate function of newly identified homologs through the analysis of phenotypes resulting from targeted mutations and misexpression, and through biochemical and gene regulation studies. Although the morphological differences between insect and vertebrate eyes undoubtedly reflect underlying distinctions in the establishment of body pattern, it is clear that exploitation of the molecular homologies between these organisms presents a powerful tool for examination of vertebrate development.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 617 732 5118; Fax: +1 617 732 5123; Email: wawersik@fas.harvard.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONVERTEBRATE EYE DEVELOPMENT AND...Pax6 IN THE FLY:...FROM FLY TO MOUSEEXTENDING THE ANALOGY: THE...CONCLUSIONS: A SIMPLE ANALOGY...REFERENCES |
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