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The Receptor Protein Tyrosine Phosphatase-mu Signaling Pathway Differentially Regulates E-cadherin, N-cadherin and R-cadherin-Mediated Axon Outgrowth

Oblander, Samantha Anne
http://rave.ohiolink.edu/etdc/view?acc_num=case1232653934

Abstract Details

2009, Doctor of Philosophy, Case Western Reserve University, Molecular Biology and Microbiology.
Understanding the complexity of how retinal ganglion cell (RGC) axons migrate out of the retina, along the retinotectal pathway to reach their target in the brain remains a central question facing neurobiologists today. RGC axon outgrowth initiated by cell adhesion molecules (CAMs) requires both adhesion to the CAM and activation of cell surface receptors initiating intracellular signaling cascades. The focus of this dissertation is on the role of E-cadherin, N-cadherin and R-cadherin in axon outgrowth in the chick visual system. In addition, we investigated the role of protein tyrosine phosphatase-mu (PTPµ) and its associated proteins in cadherin-mediated axon outgrowth. E-cadherin, N-cadherin and R-cadherin are three members of the classical cadherin family of CAMs and are expressed in the chick visual system during peak RGC axon outgrowth. N-cadherin and R-cadherin have been shown to promote neurite outgrowth. Homophilic binding of N-cadherin mediates neurite outgrowth that is dependent upon PTPµ function. PTPµ associates with E-cadherin, N-cadherin and R-cadherin. We hypothesized that E-cadherin and R-cadherin-mediated neurite outgrowth requires PTPµ. We detected E-cadherin expression in RGCs and in the tectum. In retinal organ culture studies, we demonstrated that E-cadherin promotes neurite outgrowth via homophilic binding. Conversely, R-cadherin promotes neurite outgrowth through heterophilic binding with N-cadherin. We also demonstrated that E-cadherin and R-cadherin-mediated neurite outgrowth requires PTPµ function. Observation of distinct growth cone morphologies on all three substrates, led us to hypothesize that unique signaling pathways are involved in E-cadherin, N-cadherin and R-cadherin-mediated neurite outgrowth. Inhibition studies in retinal organ cultures demonstrated that Rac1 activity is required for E-cadherin, N-cadherin and R-cadherin-mediated neurite outgrowth while Cdc42 activity is required for N-cadherin and R-cadherin-mediated neurite outgrowth via IQGAP1. The scaffolding protein IQGAP1, binds to PTPµ, Cdc42 and Rac1. PTPµ also binds to RACK1, an intracellular receptor for activated protein kinase C (PKC). We demonstrated a unique requirement for the PKCδ serine-threonine kinase in E-cadherin and R-cadherin-mediated neurite outgrowth. Investigating cadherin-mediated axon outgrowth will shed light on axon growth during development and regeneration as well as contribute to the understanding of cadherin signaling in cell-cell adhesion and cell migration.
Susann Brady-Kalnay, PhD (Advisor)
Lynn Landmesser, PhD (Committee Member)
Robert Miller, PhD (Committee Member)
Bingcheng Wang, PhD (Committee Member)
205 p.
E-CADHERIN; Neurite; Neurite Outgrowth; PTP¿¿¿¿; OUTGROWTH; R-CADHERIN-MEDIATED; RGC

Recommended Citations

Citations

  • Oblander, S. A. (2009). The Receptor Protein Tyrosine Phosphatase-mu Signaling Pathway Differentially Regulates E-cadherin, N-cadherin and R-cadherin-Mediated Axon Outgrowth [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1232653934

    APA Style (7th edition)

  • Oblander, Samantha. The Receptor Protein Tyrosine Phosphatase-mu Signaling Pathway Differentially Regulates E-cadherin, N-cadherin and R-cadherin-Mediated Axon Outgrowth. 2009. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1232653934.

    MLA Style (8th edition)

  • Oblander, Samantha. "The Receptor Protein Tyrosine Phosphatase-mu Signaling Pathway Differentially Regulates E-cadherin, N-cadherin and R-cadherin-Mediated Axon Outgrowth." Doctoral dissertation, Case Western Reserve University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1232653934

    Chicago Manual of Style (17th edition)

case1232653934
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© 2008, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.