Retinal Patterning During Eye Development

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

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Abstract

The function of the visual system is to form images in the brain. Correct photoreceptor neuron specification, patterning and morphogenesis within the retina are prerequisites for correct retinotopic axonal projections and thus image formation. The Drosophila eye serves as an excellent paradigm for many aspects of eye development, retinal biology, and disease. It is composed of a stereo-typed array of hundreds of ommatidia, or unit eyes/facets, each containing a precise arrangement of 8 photoreceptor neurons, R-cells. Establishment of their fates and their ordered arrangement requires an interplay of several signaling pathways, which have conserved similar functions during mammalian eye development. Precise retinal arrangement and morphogenesis requires a distinction of two subtypes of photoreceptors, R3 and R4, via an exquisite regulation and interplay of canonical Wnt/b-catenin signaling, the Wnt-Fz/planar cell polarity (PCP) pathway, and Notch (N)-signaling. Wnt/b-catenin signaling sets up the D/V-axis and limits eye development to a specific number of ommatidia. Wnt/Fz-PCP signaling interprets the D/V-axis information to induce R3 vs R4 neurons, during which process it has to both activate N-signaling in neighboring cells (to induce R4), and simultaneously inhibit N-activity in R3. Thus, a highly regulated Wnt/Fz and N-pathway crosstalk determines photoreceptor patterning and morphogenesis of the retina. Our prelim. data identified a novel inhibitory mechanism between Wnt and N- signaling at the level of Dsh/Dvl and the N-dependent transcription factor Su(H), CSL in mammals. Through a genome wide genetic screen, we have also uncovered a set of novel factors that modulate the function of Fz- Dsh/PCP signaling. Furthermore, the scope of this application addresses the cell biology of retinal morphology downstream of the PCP and N-pathways. The Specific Aims are: (1) To dissect an inhibitory cross-talk between the Wnt/Fz-Dsh and Notch/Su(H)-signaling pathways and the associated effects on R3/R4 specification; and (2) To use live imaging protocols, which we recently established, to get insight on how the kinases Abl (acting downstream of N-signaling), and Src64 and Pak1/3 (acting downstream of core Wnt/PCP signaling) regulate retinal morphogenesis and associated biophysical properties of cell adhesion and tissue fluidity. These Aims are well integrated and based on exciting hypotheses and preliminary data, including the mechanism of Wnt/Fz-pathway inhibition of Notch-signaling as mediated by Dsh/Dvl (Aim 1), and analyses of several kinases in retinal morphogenesis and cell adhesion as effectors of the signaling pathways studied in Aim 1 (Aim 2). A combination of in vivo studies, genetics, cell culture and biochemical experiments will be utilized together with newly developed live imaging protocols and molecular markers to achieve these goals. In the human eye, Wnt-Fz and Notch signaling are associated with many diseases and several components are associated with congenital ciliopathies affecting retinal function. Thus, the information acquired here will advance our understanding of retinal biology and will also be of medical relevance in disease areas.