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PLoS By Category | Recent PLoS Articles
Neurological Disorders - Neuroscience - Ophthalmology

ß1 Integrin-Focal Adhesion Kinase (FAK) Signaling Modulates Retinal Ganglion Cell (RGC) Survival
Published: Wednesday, October 31, 2012
Author: Andrea Rachelle C. Santos et al.

by Andrea Rachelle C. Santos, Raul G. Corredor, Betty Albo Obeso, Ephraim F. Trakhtenberg, Ying Wang, Jamie Ponmattam, Galina Dvoriantchikova, Dmitry Ivanov, Valery I. Shestopalov, Jeffrey L. Goldberg, Mary Elizabeth Fini, Michaela Livia Bajenaru

Extracellular matrix (ECM) integrity in the central nervous system (CNS) is essential for neuronal homeostasis. Signals from the ECM are transmitted to neurons through integrins, a family of cell surface receptors that mediate cell attachment to ECM. We have previously established a causal link between the activation of the matrix metalloproteinase-9 (MMP-9), degradation of laminin in the ECM of retinal ganglion cells (RGCs), and RGC death in a mouse model of retinal ischemia-reperfusion injury (RIRI). Here we investigated the role of laminin-integrin signaling in RGC survival in vitro, and after ischemia in vivo. In purified primary rat RGCs, stimulation of the ß1 integrin receptor with laminin, or agonist antibodies enhanced RGC survival in correlation with activation of ß1 integrin’s major downstream regulator, focal adhesion kinase (FAK). Furthermore, ß1 integrin binding and FAK activation were required for RGCs’ survival response to laminin. Finally, in vivo after RIRI, we observed an up-regulation of MMP-9, proteolytic degradation of laminin, decreased RGC expression of ß1 integrin, FAK and Akt dephosphorylation, and reduced expression of the pro-survival molecule bcl-xL in the period preceding RGC apoptosis. RGC death was prevented, in the context of laminin degradation, by maintaining ß1 integrin activation with agonist antibodies. Thus, disruption of homeostatic RGC-laminin interaction and signaling leads to cell death after retinal ischemia, and maintaining integrin activation may be a therapeutic approach to neuroprotection.
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