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H.E. Beggs, L. Reichardt; Retinal Lamination and Integrity of the Lens Capsule Basement Membrane Requires Focal Adhesion Kinase Signaling . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3165.
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Purpose: Previously we showed that targeted deletion of focal adhesion kinase (FAK) from the developing forebrain resulted in localized disruption of the cortical basement membrane. As a result, neurons invaded the marginal zone and produced cortical lamination defects resembling type II lissencephaly as seen in congenital muscular dystrophy. Since congenital muscular dystrophy is known to produce ophthalmological abnormalities in humans (including microphthalmia, retinal dysplasia, inner limiting membrane (ILM) discontinuity, persistent hyperplastic vitreous (PHPV) and gliosis), we asked whether deletion of FAK in the developing mouse eye would produce a similar ocular phenotype. Methods:We generated a conditional "floxed" knockout allele of FAK and mated this line to Nestin Cre and Six3 Cre mouse lines. These lines deleted FAK in the developing retina and lens or retina only, respectively. Results:Conditional deletion of FAK during eye development using Nestin–Cre results in ophthalmological abnormalities including severe retinal dysplasia, reactive gliosis, neovascularization, complete lens degradation and microphthalmia. These defects can be attributed to disruption of two important basement membranes: the retinal inner–limiting membrane organized by Mueller glia endfeet and the lens capsule basement membrane organized by lens fiber epithelial cells. Deletion of FAK in the retina but not the lens using a Six3–Cre line produces similar retinal defects. However, the presence of a normal lens rescues eye size in these animals, suggesting that defective lens development is responsible for microphthalmia. Conclusions:These results indicate that FAK is critical for regulation and maintenance of basement membranes in the developing eye. Loss of this pivotal regulator of cell–matrix adhesion sites to the cytoskeleton may represent a fundamental defect in the ophthalmological abnormalities seen in patients with congenital muscular dystrophy as well as other ocular diseases involving disrupted basement membrane organization.
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