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.
Highlights
The Extracellular matrix (ECM) protein laminin is present in many areas of the central nervous system (CNS), during development
We and others have shown that laminin degradation after a variety of insults including retinal ischemia, and glaucoma is associated with up-regulation of a specific matrix metalloproteinase, matrix metalloproteinase-9 (MMP-9), and decreased retinal ganglion cells (RGCs) survival in those animal models [7,8,9,10]
Apoptosis is involved in neuronal cell death in animal models of transient retinal ischemia and has been detected in the ganglion cell layer (GCL), inner nuclear cell layer (INL), and the outer nuclear layer (ONL) of the retina [25,26,27,28]
Summary
The ECM protein laminin is present in many areas of the CNS, during development. Laminin continues to be an important, abundant component of the ECM in adult CNS. Laminins are critical to neurite outgrowth and to the structure of the neuronal synapse [1]. They are a major component of ECM and basement membranes in the retina [2], being involved in RGC migration and subsequent development [3]. Laminin chains a2 [4], and b1 [5] have been directly associated with RGCs in the retina. Laminin promotes survival and axon outgrowth in purified RGCs in culture [6]
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