Two fundamental organizing principles of axonal connections in the mammalian visual system are eye-specific connections and retinotopic maps. Eye-specific connections are patterned in a manner that keeps primary inputs from the two eyes segregated, allowing them to be brought together in selective manners for higher order processing to generate binocular vision. Retinotopic maps are organized to maintain the spatial arrangement of retinal ganglion cells (RGCs) in the retina through the orderly terminations of their axons to neighboring parts of their targets, thereby creating a representation of the visual world in the brain critical for high acuity vision. This proposal builds upon recent findings to study the development of these two organizing principles, employing the mouse as a model system to make use of genetic approaches including conditional gain- and loss-of function analyses using selectively patterned transgene activation and gene inactivation. The studies proposed in Aim 1 will define the roles of Isl1, Isl2 and Zic2 in the genetic specification of the magnitude and source of ipsilateral retinal projections to the brain.
Aim 2 will define the mechanism by which EphB receptors control laterality pathfinding decisions of RGC axon growth cones at the optic chiasm.
Aims 3 and 4 will assess the proposed bifunctional action of ephrin-B1 in controlling dorsal (D)-ventral (V) retinotopic mapping, and select between models of EphB receptor function in controlling RGC axon responses to ephrin-Bl.
Aim 5 proposes continuing a microarray screen using tissue from D and V wild type retina and mutants with D-V patterning defects to identify additional genes potentially involved in D-V retinal patterning and mapping. The findings from Aims 1 and 2 will establish a hierarchy of genetic regulation of binocular vision and the related molecular control of RGC axon pathfinding at the optic chiasm. The findings from Aims 3, 4 and 5 will define the molecular mechanisms controlling retinotopic mapping of the D-V axis of the retina in central visual targets in the brain, and new genes involved in this patterning. The two sets of Aims are related in important ways, including that they address the fundamental organizing principles of the visual system, study the same populations of RGCs, make use of the same genetically altered mice, and address issues related at a genetic, molecular, and conceptual level. Therefore, the proposed studies complement one another and make efficient use of many lines of genetically altered mice. ? ?
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