Proneural basic helix-loop-helix (bHLH) transcription factors function as transcriptional activators and are required for the development of specific retinal neuron subtypes. For example, the Ath5 gene is required for the differentiation of retinal ganglion cells (RGC), an early born cell type, while NeuroD contributes to the development of amacrine cells, a later born cell type. However, the mechanisms by which bHLH factors promote retinal neuron differentiation, and how they contribute to the ordered sequence of retinal histogenesis is less well defined. We have identified both transcriptional and post-translational mechanisms that regulate when during retinal development bHLH factors are active. If Ath5 or NeuroD are active during early retinal development they promote differentiation of RGCs, however if they are active later, they promote later born cell types, consistent with the idea that progenitor competence changes over developmental time. Furthermore we found that bHLH factors regulate retinal neurogenesis by activating the expression of downstream target genes that are involved in executing the neuronal differentiation program within retinal progenitor cells. ? ? Much remains to be learned about how the activity of bHLH factors is regulated and which genes are transcribed in response to bHLH activity. We propose to investigate both transcriptional and post-translational mechanisms for regulating bHLH activity during retinal neurogenesis. In addition, since our understanding of the genetic pathway downstream of proneural bHLH function is incomplete, we have performed a screen to identify additional genes that are regulated by Ath5 and NeuroD. We propose to analyze these putative targets and determine how they contribute to retinal neurogenesis. ? ? By defining the mechanisms controlling normal retinogenesis, we may gain a better understanding of how these problems can be disrupted in pathological situations. For example, a number of congenital disorders of vision, such as retinal dystrophies, may be caused by problems with the early genesis and differentiation of retinal neurons. Ultimately, this work may help us understand and manipulate the differentiation of retinal stem cells or progenitors for the treatment of degenerative diseases of the retina, such as glaucoma and retinitis pigmentosa. ? ?
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