The Microphthalmia-associated Transcription Factor Mitf, the Wnt-pathway effector Arm/?-Catenin, and the Hippo-pathway-regulated transcriptional co-activator Yki control the binary choice between neural epithelium (retina) and non-neural support tissue (peripodial epithelium or PE) in the developing eye disc of Drosophila. Specifically, these factors function as promoters of PE fate and suppressors of retina fate. Using the tools of the Drosophila model, we propose to carry out detailed genetic and molecular analyses of these factors' role in PE determination (Specific Aim 1) and investigate how control of their phosphorylation state (Specific Aim 2) and mRNA stability/translation (Specific Aim 3) regulate their function. Our work will define for the first time the genetic network for eye peripodial specification, the eye-Peripodial Determination Network or ePDN, and lead to the discovery of novel network components. Strikingly, homologous factors play an analogous role during development of the mammalian eye, where MITF, ?-CATENIN, YAP and TAZ, and TEAD specify the Retinal Pigmented Epithelium (RPE) of the optic vesicle. These findings point to an ancient evolutionary relationship between the genetic networks that define accessory support cells of photoreceptor neurons in both flies and vertebrates. Based on this conservation, we believe that our studies will also generate insights into RPE formation.
The genetic networks that control fate determination in the Peripodial Epithelium (PE) of Drosophila and in the Retinal Pigmented Epithelium (RPE) of the vertebrate eye are significantly conserved. This work will characterize the genetic network at work in the PE, and thus identify potential components of the RPE determining network and candidate contributing-factors for eye diseases linked to RPE dedifferentiation and dysfunction.
