Understanding the molecular mechanisms which control the development of the eye and visual pathways will serve as the foundation for the development of novel strategies for the prevention and treatment of congenital diseases affecting vision. There is growing evidence that early patterning events in the neural tube regulate cell fate choices and are critical for establishing the positional cues which guide the formation of neuronal connections. The applicant has identified two transcription factors, brain factors-1 and -2 (BF-1 and BF-2), that have unique expression patterns in the developing optic diverticulum. BF-1 is restricted to the nasal (anterior) half of the optic vesicle and stalk neuroepithelium while BF-2 is restricted to the temporal (posterior) half. In order to examine their function in eye development, the applicant has generated mice with a targeted deletion in each gene. Preliminary studies suggest an important role for BF-1 in the patterning of the optic diverticulum along both the dorsal-ventral and anterior-posterior axes. They have also found anomalies in the projections of retinal ganglion cell (RGC) axons in both the BF-1 (-/-) mutant and the BF-2 (-/-) mutant. They propose to examine mechanisms regulating the patterning of the developing optic diverticulum by evaluating the hypothesis that BF-1 and BF-2 function to link the patterning of the optic diverticulum to the molecules which guide the projection of RGC axons.
The specific aims are to: (1) investigate the mechanisms underlying the abnormal dorsal-ventral patterning of the optic diverticulum in the BF-1 (-/-) mutant by assessing the role of sonic hedgehog as a mediator of BF-1 function, using explants of forebrain from mutant and normal embryos; (2) investigate the consequences of deleting BF-2 on eye development by examining mutant mice to determine the basis for anomalous RGC pathfinding in the region of the optic chiasm; and (3) investigate the mechanisms by which BF-1 and BF-2 control AP patterning in the retina by examining anomalies in RGC pathfinding in mutant mice and determining the molecular basis for these defects.
