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

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012251-06
Application #
6726164
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Oberdorfer, Michael
Project Start
1998-09-30
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
6
Fiscal Year
2004
Total Cost
$344,250
Indirect Cost
Name
Case Western Reserve University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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
Phillips-Mason, Polly J; Mourton, Tracy; Major, Denice L et al. (2008) BCCIP associates with the receptor protein tyrosine phosphatase PTPmu. J Cell Biochem 105:1059-72
Yu, Jianshi; Becka, Scott; Zhang, Peng et al. (2008) Tumor-derived extracellular mutations of PTPRT /PTPrho are defective in cell adhesion. Mol Cancer Res 6:1106-13
Oblander, Samantha A; Ensslen-Craig, Sonya E; Longo, Frank M et al. (2007) E-cadherin promotes retinal ganglion cell neurite outgrowth in a protein tyrosine phosphatase-mu-dependent manner. Mol Cell Neurosci 34:481-92
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
Xie, Youmei; Massa, Stephen M; Ensslen-Craig, Sonya E et al. (2006) Protein-tyrosine phosphatase (PTP) wedge domain peptides: a novel approach for inhibition of PTP function and augmentation of protein-tyrosine kinase function. J Biol Chem 281:16482-92
Phillips-Mason, Polly J; Gates, Theresa J; Major, Denice L et al. (2006) The receptor protein-tyrosine phosphatase PTPmu interacts with IQGAP1. J Biol Chem 281:4903-10
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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