Dorsal-Ventral retinal patterning: genetic mechanisms for the development of a topographic map

Topographic connections of retinal axons with their brain targets allow us to perceive a spatially organized image of the visual world. Achieving this precise retinotopic axon targeting during development first requires the patterning of origin (retina) and target (brain) tissues along anterior-posterior (A-P) and dorsal-ventral (D-V) axes, such that individual cells of both tissues acquire a molecularly specified positional identity. The research presented in my dissertation addresses the processes involved in patterning the dorsal-ventral axis of the retina and forming dorsal-ventral retinotopic projections. First, I studied what tissues and signals are involved in the initiation of dorsal polarity. I found that the dorsolateral region of the optic vesicle is the first domain to upregulate dorsal-specific transcription factors. My expression studies, combined with my fate map experiments, suggested that these dorsolateral optic vesicle cells continue expressing dorsal markers throughout optic vesicle morphogenesis, and eventually contribute to dorsal and central retina. I also showed that the BMP family gene gdf6a is necessary for initiation of dorsal retinal fate. Importantly, I found that gdf6a acts early during optic vesicle evagination (10-12 hpf) when it is expressed in the extraocular head ectoderm overlying the region of dorsolateral optic vesicle that first expresses dorsal-specific transcription factors. Finally, I showed that the bmp2b gene is also necessary for dorsal retinal fate initiation, acting upstream of gdf6a. Secondly, I performed a forward genetic screen to search for novel genes that specify the dorsal-ventral axis of the retina. By screening for mutants with altered expression of D-V markers, I identified a novel gene, bigtop, required for dorsal-ventral retinal patterning, eye development, and retinotectal projections. This mutation was mapped to a four-megabase region on chromosome two. My studies addressed the following question: how is the retina patterned early during development in order to specify retinal ganglion cells with positional fate? Altogether, my studies advanced the field of D-V retinal patterning by identifying an extraocular dorsal retinal initiation signal, uncovering the role of bmp2b in dorsal retinal initiation, and identifying a novel mutant necessary for D-V patterning.