Retina: Lilliputian and the control of retinal neurogenesis

Law, William

Abstract

A fundamental question in developmental biology is the control of neurogenesis. Proper neural development underlies the basic cellular processes required within all cells of the mature nervous system. Neurophysiology, and even broader processes such as consciousness or intelligence intimately depend upon proper developmental control of cells within the nervous system. The long term goal of this project is a deeper understanding of retinal neurogenesis, with the hope that the research proposed will ultimately lead to new diagnostic tools and/or therapeutic targets for retinal regeneration in patients with retinal degeneration or damage. The developing eye of the fruit-fly Drosophila melanogaster serves as an excellent system to model how neurogenesis is controlled within a developing nervous tissue. Proper retinal neurogenesis in Drosophila begins with the induction of the founding neural cell type through the precise expression of the proneural transcription factor atonal (ato) in flies (Atonal homolog 5, Ath5 in vertebrates) [1, 2]. This expression is critical for proper retinal development. Therefore, we have used an ato eye phenotype as the basis for a genetic screen in the fly eye. This proposal centers on one of the mutants isolated in this screen: mutations in the lilliputian (lilli) gene. lilli encodes the Drosophila homolog of the FMR2 protein, and is the only member of the FMR2/AF4 gene family of transcription factors found in flies [3, 4]. Mutation in members of the AF4/FMR2 gene family in humans are involved in both acute lymphoblastic leukemia and mental retardation, though little is known about the specific roles these proteins have in disease etiology, or which cellular processes they regulate [5, 6]. This proposal attempts to study how lilli functions during the specification of retinal founder cell development through one specific aim: 1) Analysis of atonal transcriptional activation/maintenance by Lilli. Our preliminary data show that proper lilli function is required for ato transcription in the developing fly eye. Our working hypothesis is that Lilli mediates atonal transcription through a direct interaction with atonal regulatory sequences and Atonal binding partners. To begin to test this hypothesis, we will examine whether Lilli binds to specific atonal regulatory sequences and transcriptional cofactors, and determine which signals regulate this Lilli-mediated atonal transcription in the developing Drosophila retina.The process of initiating retinal development is very well conserved throughout species. As Lilliputian is the only member of the AF4/FMR2 family of proteins in Drosophila, a deeper understanding of how Drosophila Lilliputian is involved in initiating retinal development will likely be of very broad relevance to our understanding of the process of mammalian retinal development, and may lead to novel diagnostic tools and/or therapeutic targets for patients with inherited retinal degeneration or damage. Further, our preliminary data suggests that our results obtained so far from our studies involving Drosophila retinal development and Lilliputian function are not solely limited to developing retinal cells, and may be broadly applicable to a variety of Drosophila nervous tissues, thus expanding our understanding of how mutations in the lilliputian homolog FMR2 are involved in the clinical symptoms of FRAXE mental retardation syndrome, and again may lead to novel diagnostic tools and/or therapeutic targets for these patients as well. ? ? ?