The generation of meaningful behavioral responses to visual stimuli requires the appropriate topographic ordering of synaptic connections throughout the visual pathway. Visual information is routed through the axons of retinal ganglion cells directly from the retina to the superior colliculus (SC) of mice, or its homologue in non-mammalian vertebrates, the optic tectum. The proposed studies are directed toward defining the molecules and mechanisms involved in establishing topographic connections from the retina to the mouse superior colliculus or the chick optic tectum. The hypotheses will be tested with complementary loss of function and gain of analyses at stages covering the critical development events, and when appropriate, in vitro experiments to test the effect of specific activities and molecules on retinal axon growth, targeting, and branching. The four specific aims are:
Aim 1. To demonstrate the role of EphA receptors in controlling A-P topographic specificity. Hypothesis: The level of EphA receptors expressed by RGCs controls the mapping of their axons along the rostral-caudal axis of the SC.
Aim 2. To determine the role of BDNF as a promoter of retinal axon branching and a potential regulator of topographical-specific branching. Hypothesis: BDNF induces retinal axon branching through a trkB mediated mechanism, and acts in vivo to complement ephrin-A ligands to generate the observed topographic specificity in retinal axon branching along the A-P axis of the tectum/SC.
Aim 3. To define the roles of EphB receptors and ephrin B-1 in topographic mapping of retinal axons along the medial -lateral axis of the tectum /SC. Hypothesis: Ephrin-B1 acts through an attractive mechanism to promote the mapping of the ventral-dorsal axis of the retina along the medial-lateral (M-L) axis of the tectum/SC. This attractive influence of ephrin-B1 is mediated by EphB2 and EphB3 on RGC axons. In principle, this putative bi-functional action of ephrin-B1 would be sufficient to generate topographic mapping of RGC axons along the M-L axis. Finally, we consider the possibility that bi-directional signaling of ephrin-B1 may have a role in mapping.
Aim 4. To determine the molecular control of retinal axon patterning in the diencephalon. Hypothesis: Slit proteins influence the patterning of retinal projections in the diencephalon through a Robo mediated repellent action.
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