| One of the fundamental issues in neural development is how neurogenesis is controlled intrinsically by transcriptional network. The neural retina is an exceptional model to study central nervous system development because of its easy accessibility and the well organized laminar structure. This work is aimed at identifying transcription factors (TFs) critical for retinogenesis and at understanding how they coordinate to mediate this process. Particularly, I explore the roles of POU-homeodomain (POU-HD) TFs and LIM-HD TFs in the development of retinal ganglion cells (RGCs), the only projection neurons in the retina.;The first part of this study investigates the functional relationship between two closely related POU-HD TFs Brn3b and Brn3a. By knocking the brn3a coding sequence (brn3aki) into the brn3b locus, I demonstrate that the brn3a ki can fully rescue the retinal defects associated with brn3b-null mice, and that the unique roles of these two factors in retina development result from their distinct spatiotemporal expression patterns. I also show that during normal development, Brn3b regulates the expression of Brn3a in RGCs. These findings shed light on the complex self- and reciprocal-regulations between Brn3 factors.;In the second portion of this study, I show that Islet1 (Isl1), a LIM-HD TF, is co-expressed with Brn3b in nascent RGCs. Specific removal Isl1 in retina results in the disrupted RGC axon growth and major RGC loss, which strikingly resemble the phenotypes of brn3b-null mice. More severe retinal abnormalities are detected in Isl1 and brn3b double null mice. Furthermore, using in vivo chromatin immunoprecipitation (ChIP), I show that both factors simultaneously bind to the promoters of RGC specific genes and are required for their proper expression. These data indicate the cooperative mechanism of Isl1 and Brn3b in regulating the gene cascade of RGC differentiation.;The last part of this study extends to the transcriptional control of RGC axon guidance. I reveal that in Isl1-null mice, the contralateral projecting RGCs mistakenly choose the ipsilateral trajectory at the optic chiasm, but still make correct connections in the contralateral targeting area. These results suggest that the bilateral targeting property is intrinsically encoded in RGCs. |
