Tyrosine phosphorylation is key to development of the visual system. Eph receptor tyrosine kinases and their ephrin ligands help guide retinal ganglion cell axons to proper regions of the tectum. We have recently shown that the receptor protein tyrosine phosphatase, PTPu, is also likely to be a critical player in axon growth and guidance of retinal ganglion cells. PTPu is a member of the Ig superfamily of cell adhesion molecules (CAMs) and a tyrosine phosphatase suggesting that it sends signals directly in response to adhesion. PTPu mediates cell-cell aggregation through homophilic binding and associates with cadherins. We demonstrated that PTPu is expressed by retinal ganglion cells and that PTPu is one of an elite class of adhesion molecules that promotes neurite outgrowth. Equally important, PTPu regulates neurite outgrowth on N-cadherin, a CAM required for proper retinotectal development. Most importantly, PTPu is a permissive substrate for neurite outgrowth of nasal retinal ganglion cell neurons while it is inhibitory to temporal neurons. In order to understand the role of PTPu in development of the visual system, we propose the following specific aims: I. Does PTPu play a role in retinal development? A. Characterize the developmental expression pattern of PTPu in the retina, optic nerve and tectum of the chick visual system B. Investigate the role of PTPu in lamination of the chick retina during development in organ culture and in ovo II. What role does PTPu play in spatiotemporal patterning of the visual system? A. Investigate the role of PTPu in pathfinding of chick retinal ganglion cells as they project to the optic tectum in ovo B. Determine how PTPu phosphatase activity regulates both nasal and temporal neurite outgrowth on a PTPu substrate in retinal explant cultures III. Is the PTPu interacting protein, RACK1, involved in sending signals that regulate neurite outgrowth on a PTPu substrate? A. Analyze the role of RACK 1 in PTPu adhesion-dependent signaling in retinal cells B. Utilize inhibitors of RACK1/PKC and src to determine if they play a role in PTPu-dependent neurite outgrowth C. Determine if PTPu utilizes the PKC or sic signaling pathways to inhibit neurite outgrowth of temporal neurons

National Institute of Health (NIH)
National Eye Institute (NEI)
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Special Emphasis Panel (ZRG1-VISC (01))
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Oberdorfer, Michael
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Case Western Reserve University
Schools of Medicine
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Oblander, Samantha A; Brady-Kalnay, Susann M (2010) Distinct PTPmu-associated signaling molecules differentially regulate neurite outgrowth on E-, N-, and R-cadherin. Mol Cell Neurosci 44:78-93
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Major, Denice L; Brady-Kalnay, Susann M (2007) Rho GTPases regulate PTPmu-mediated nasal neurite outgrowth and temporal repulsion of retinal ganglion cell neurons. Mol Cell Neurosci 34:453-67
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Ensslen-Craig, Sonya E; Brady-Kalnay, Susann M (2005) PTP mu expression and catalytic activity are required for PTP mu-mediated neurite outgrowth and repulsion. Mol Cell Neurosci 28:177-88
Ensslen-Craig, Sonya E; Brady-Kalnay, Susann M (2004) Receptor protein tyrosine phosphatases regulate neural development and axon guidance. Dev Biol 275:12-22
Ensslen, Sonya E; Brady-Kalnay, Susann M (2004) PTPmu signaling via PKCdelta is instructive for retinal ganglion cell guidance. Mol Cell Neurosci 25:558-71

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