The Müller cells (MCs) have a key role in retinal homeostasis. They are polarized with an apical compartment facing the subretinal space, and a basal surface adhering to the inner limiting membrane (ILM). Disruption of either compartment leads to activation of MCs and pathobiological consequences leading to vision loss. Laminins are key organizing molecules of basement membranes (BM), such as the ILM, and they serve as attachment sites for cell adhesion, polarity and proliferation. We produced null mutations in mice of two laminin genes, Lamb2 and Lamc3, and found that these molecules are necessary for normal retinal development. The retinal defects in the Lamb2/c3 nulls include: ILM malformation; MC disorganization and OLM disruption; photoreceptor dysgenesis; and progressive pathology in the inner retina. Our long-range goal is to understand the molecular contributions of laminin to the development and stability of MC organization, in particular, as it relates to the functional architecture of the retina. Our immediate goal is to assess the organizing hypothesis that Müller cell-laminin interactions are critical for: 1) establishing MC polarity; 2) maintaining MC subcellular organization and 3) stabilizing the structural integrity of the neural retina.

Our work will contribute significantly to the understanding of several congenital disorders o affecting the eye including some forms of Walker-Warburg, Bardet-Biedl, Pierson's Syndrome as well as the pathophysiology of gliosis and proliferative vitreoretinopathy.

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8. Saghizadeh, M., Soleymani, S., Harounian, A., Bhakta, B., Troyanovsky, S.M., Brunken, W.J., Pellegrini,G., and Ljubimov, A.V. Alterations of epithelial stem cell marker patterns in human diabetic corneas and effects of c-met gene therapy. Molecular Vision 17:2177-2190. 2011
9. Yebra, M., Diaferia, G.R., Montgomery, A.M., Kaido, T., Brunken, W.J., Koch, M., Hardiman, G., Crisa, L., and Cirulli, V. Endothelium-Derived Netrin-4 Supports Pancreatic Epithelial Cell Adhesion and Differentiation through Integrins α2β1 and α3β1. PLoS One 6(7):e22750. 2011
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