research summary









The Drosophila eye is an ideal model for studying pattern formation, growth regulation, and morphogenesis during development of the nervous system. We are interested in understanding the moleculargenetic basis of three key events in eye development: (1) patterning and growth of early eye disc, (2) regulation of retinal neurogenesis, and (3) morphogenesis and maintenance of photoreceptor cell polarity.

1.  Dorsoventral patterning and growth in early eye disc

The Drosophila eye consists of approximately 800 unit eyes, called ommatidia. The adult eye develops from the retinal primordium called eye imaginal disc. The eye field is compartmentalized into dorsal and ventral domains, and the dorsoventral (DV) boundary is specified by antagonistic interactions of dorsal and ventral genes.  Formation of the DV boundary plays a crucial role for induction of growth and patterning of early eye disc by activating Notch signaling. Thus, loss of DV boundary leads to the failure of eye development. We have found that Lobe is one of the genes involved in mediating the Notch function in controlling growth and survival of early eye disc. In addition, Drosophila homolog of Translationally Controlled Tumor Protein (TCTP) acts as a critical component in the TOR signaling pathway and eye growth. We are currently studying the relationship between Lobe and TCTP as well as the function of new genes interacting with Lobe and TCTP to gain insights into signaling events in early eye development.

                                    2.  Genetic control of retinal neurogenesis

After DV patterning, retinal neurogenesis is initiated at the posterior margin of the undifferentiated eye disc. The site of neurogenesis, named morphogenetic furrow, proceeds anteriorly, generating regular arrays of photoreceptor neuronclusters (ommatidia) behind the furrow. This process is induced by the atonal proneural gene of a basic helix-loop-helix (bHLH) transcription factor family. We have found that atonal expression posterior to the furrow is repressed by Bar homeobox proteins to prevent ectopic neural differentiation. In the absence of Bar homeobox proteins, atonal expression is ectopically induced to generate excess photoreceptors. We are analyzing the mechanism of atonal repression by Bar and other target genes regulated by Bar.

Atonal is known to play a proneural role by heterodimerizing with another bHLH protein Daughterless (Da). Interestingly, we have found that the Da level is elevated in the cells surrounding the neuronal precursor cells. This high level of Da is required for lateral inhibition of atonal expression, thereby preventing ectopic neurogenesis. Da upregulation depends on Notch signaling and in turn induces Notch signaling for ato repression. Thus, the dual functions of Da as a proneural and anti-proneural factor are crucial for initial neural patterning in the eye. More detailed molecular mechanisms of Da proteins anti-proneural function remain to be characterized.

                                       3.  Cell polarity and photoreceptor morphogenesis

Apical basal cell polarity is a fundamental feature of most cell types including the photoreceptor cell. Retinal cells undergo a remarkable morphogenetic process to establish the highly polarized neuronal cell structure. We have shown that a transmembrane protein Crumbs provides an essential positional cue for apical-basal organization of photoreceptors. For instance, loss of crumbs, one of conserved polarity genes, results in disorganization of rhabdomere and apical cell junctions.  Interestingly, mutations in a human crumbs homolog cause retinal diseases such as Retinitis Pigmentosa 12 (RP12) and Leber Congenital Amaurosis (LCA). Thus, understanding of polarity gene functions in developing Drosophila photoreceptors might provide an insight into the molecular basis of important retinal diseases in humans.

Interaction of Crumbs and other conserved apical proteins are important for morphogenesis of photoreceptors. Currently, we focus on studying how Crumbs protein complexes are targeted to specific membrane domains and utilizing genetic approaches to identify candidate genes that might be related to retinal diseases like RP and LCA.





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