Regulation of Retinal Neurogenesis by Foxp1

PROJECT SUMMARY: Normal retinal function and vision depends upon generation of multiple classes of retinal cells during development. A central challenge is to define molecular mechanisms that enable a diversity of neurons and glia to be generated from progenitors in correct proportions during development. Prior studies have shown that progenitors undergo changes in competence to generate retinal cell types, but knowledge is incomplete regarding factors that function to regulate temporal patterning of progenitors to drive changes in competence. We thus hypothesize that Foxp1 functions as an early temporal transcription factor, and that temporally regulated Foxp1 gene expression governs the formation of retinal cell types generated during early retinal development, such as retinal ganglion cells, horizontal cells, cone photoreceptors and early-born amacrine cells. To test this in developing mouse retina, we will use genetic approaches to achieve loss or gain of Foxp1 to: 1) Define Foxp1 targets and changes in chromatin accessibility, 2) Determine whether Foxp1 can reactivate competence to generate early-born retinal cell types in late RPCs, and 3) Determine whether Dicer regulates regulates temporal expression of Foxp1. This study will provide mechanistic insight into how Foxp1 functions in progenitors to regulate the genesis of early-born retinal neurons, and may facilitate strategies to generate early retinal cell types lost to disease or injury, such as retinal ganglion cells and cones.