Proneural bHLH proteins are master regulators of neural development that control the differentiation of rod and cone photoreceptor cells in the retina as well as retinal ganglion cells and amacrine cells, and also corneal nerves. These cells are required for vision and proper maintenance of the eye. Proneural bHLH proteins are transcription factors that only bind DNA in heterodimers with a ubiquitous class of E-protein bHLH proteins and are antagonized by the ID-class of HLH proteins. Developmental genetic studies of the mechanisms of Extramacrochaetae function during eye development and differentiation will elucidate the unexpected new pathways of ID-protein function that have been discovered. To understand the function of this network of interacting proteins, biochemical methods will be used to determine the respective affinities of representative proteins for one another, and protein-protein interactions studied in tissue preparations to verify which protein associations occur in vivo in correlation with periods of active neurogenesis and which occur when neural development is quiescent. Because expression levels of the various proteins are regulated through protein stability, and potentially through modulation of dimerization affinities, the unidentified factors regulating stability and activity will be sought through genetic screens for modifiers of the ID-protein Extramacrochaetae and identified using a next-generation sequencing approach. These studies are expected to reveal new regulators of neural development that are important in the eye. These studies are expected to suggest new routes to maintain and regenerate healthy eye tissues.
Development and health of the eye relies on nerve cells in the retina and cornea. Neural development depends on a network of key factors that control neural gene expression. The molecular functions of these factors will be studied, and the mechanisms that modulate their stabilities and activities identified, with a view to maintaining and regenerating healthy eye function.