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Title page for ETD etd-12022010-212158


Type of Document Dissertation
Author Perdigoto, Ana Luisa Jordao
URN etd-12022010-212158
Title Mechanisms of neurite outgrowth inhibition by Myelin-associated glycoprotein
Degree PhD
Department Biochemistry
Advisory Committee
Advisor Name Title
Bruce Carter Committee Chair
Donna Webb Committee Member
graham carpenter Committee Member
Jennifer Pietenpol Committee Member
scott heibert Committee Member
Keywords
  • cortical neurons
  • PTEN
  • Myelin-associated glycoprotein
  • neurite outgrowth
  • AKT
Date of Defense 2010-09-14
Availability unrestricted
Abstract
Axonal regeneration in the central nervous system is prevented, in part, by inhibitory proteins expressed by myelin, including Myelin-associated glycoprotein (MAG). Although injury to the corticospinal tract can result in permanent disability, little is known regarding the mechanisms by which MAG affects cortical neurons. Here, we demonstrate that cortical neurons plated on MAG expressing CHO cells, exhibit a striking reduction in process outgrowth. Interestingly, none of the receptors previously implicated in MAG signaling, including the p75 neurotrophin receptor or gangliosides, contributed significantly to MAG-mediated inhibition. However, blocking the small GTPase Rho or its downstream effector kinase, ROCK, partially reversed the effects of MAG on the neurons. In addition, we identified the lipid phosphatase PTEN as a mediator of MAG’s inhibitory effects on neurite outgrowth. Knockdown or gene deletion of PTEN or over expression of activated AKT in cortical neurons resulted in significant, although partial, rescue of neurite outgrowth on MAG-CHO cells. PTEN knockout and Rho inactivation resulted in an additive effect on reversal of neurite outgrowth inhibition by MAG, suggesting that both molecules contribute to inhibition of cortical neurite outgrowth by MAG. Moreover, MAG decreased the levels of phospho-Akt, suggesting that it activates PTEN in the neurons. Taken together, these results suggest a novel pathway activated by MAG in cortical neurons involving the PTEN/PI3K/AKT axis.

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