The molecular mechanisms underlying visual-system development are only beginning to be understood. The long-term objectives of this work are the identification and characterization of molecules that govern the differentiation of neuronal classes in the visual pathway. The vertebrate retina is composed of over 50 neuronal cell types that fall into 6 major classes. This proposal focuses on one prominent class, the retinal ganglion cells, which connect the eye to the brain. The current model of retinal neurogenesis proposes that cell classes are generated during development from multipotential progenitors in an invariant temporal order. Ganglion cells are always born first; they emerge from a sheet of undifferentiated progenitor cells in the form of a wave that sweeps across the embryonic eye. In this grant, we will use a genetic approach in zebrafish, to investigate the molecular interactions that underlie the ganglion-cell differentiation wave. The recently discovered transcription factor Ath5 is of central importance, since its mutation in the zebrafish mutant lakritz eliminates all ganglion cells. We will test its interactions with the factors Shh, Twhh, Fgfl, and Brn3c, which have been implicated in ganglion-cell genesis. We will further ask whether Ath5 is also involved in subsequent steps of differentiation of retinal ganglion cells. Finally, we will attempt to discover novel genes in a mutagenesis screen taking advantage of a transgenic zebrafish line that expresses GFP in ganglion cells. These studies will establish a genetic pathway of factors involved in determination, differentiation, and diversification of retinal ganglion cells. Health-relatedness. This approach may lead a way to isolating genes involved in diseases of the human retina, such as glaucoma and optic-nerve hypoplasia, for which there are currently no cures
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