title: β1 integrin-focal adhesion kinase (FAK) signaling modulates retinal ganglion cell (RGC) survival.
abstract: 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 β1 integrin receptor with laminin, or agonist antibodies enhanced RGC survival in correlation with activation of β1 integrin's major downstream regulator, focal adhesion kinase (FAK). Furthermore, β1 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 β1 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 β1 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.
authors.affiliation: Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Andrea Rachelle C
authors.initials: AR
authors.lastname: Santos
authors.forename: Raul G
authors.initials: RG
authors.lastname: Corredor
authors.forename: Betty Albo
authors.initials: BA
authors.lastname: Obeso
authors.forename: Ephraim F
authors.initials: EF
authors.lastname: Trakhtenberg
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jamie
authors.initials: J
authors.lastname: Ponmattam
authors.forename: Galina
authors.initials: G
authors.lastname: Dvoriantchikova
authors.forename: Dmitry
authors.initials: D
authors.lastname: Ivanov
authors.forename: Valery I
authors.initials: VI
authors.lastname: Shestopalov
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Goldberg
authors.forename: Mary Elizabeth
authors.initials: ME
authors.lastname: Fini
authors.forename: Michaela Livia
authors.initials: ML
authors.lastname: Bajenaru
mesh_terms: D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D002470:Cell Survival; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D019012:Integrin beta1 / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: D019012:Integrin beta1; D007797:Laminin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020780:Matrix Metalloproteinase 9