Diseases affecting the function of the visual system have a major health and economic impact on society. Congenital abnormalities lead to lifelong disability, while degenerative diseases of the eye are a growing problem in the aging population. The ability to develop new treatment and prevention strategies for these problems depends upon an understanding of how the visual system develops and functions. While much is known about the sequence of events during the development of the eye and the optic nerve, relatively little is known about the molecular mechanisms which direct these processes. The applicant has identified two novel transcription factors, called brain factors-1 and 2 (BF-1 and BF-2) which are expressed in restricted regions of the forebrain neuroepithelium during embryogenesis. They have a unique pattern of expression in the developing retina and optic stalk. BF-1 is restricted to the nasal half of the retinal neuroepithelium while BF-2 is restricted to the temporal half. Preliminary analysis of mouse embryos with a targeted deletion of BF-1 shows disordered development of the nasal retina, suggesting that these genes play important roles during eye development. This proposal will examine the molecular mechanisms by which BF-1 and BF-2 control two key processes of eye development, (1) the proliferation and differentiation of retinal progenitors and (2) the guidance of retinal ganglion cell axons to their targets in the brain.
The specific aims are: (1) to examine the consequences of a BF-1 knockout on the development of the eye and optic nerve by studying the alteration in the morphology and patterns of gene expression in mutant mouse embryos; (2) to generate mice which are deleted in the BF-2 gene in order to examine the function of BF-2 in eye development; (3) to elucidate the role of BF-1 in regulating the proliferation and differentiation of retinal neuroepithelial cells in cell culture by examining the possible alterations in the response of BF-1 mutant cells to regulatory factors; and (4) to identify targets of BF-1 in the retina which mediate its function in growth control and in guiding axon growth.
