The lens capsule is a modified basement membrane that completely surrounds the ocular lens. It is known that this extracellular matrix is important for both the structure and biomechanics of the lens in addition to providing informational cues to maintain lens cell phenotype. This review covers the development and structure of the lens capsule, lens diseases associated with mutations in extracellular matrix genes and the role of the capsule in lens function including those proposed for visual accommodation, selective permeability to infectious agents, and cell signaling.

The Pax6 transcription factor functions early during embryogenesis to control key steps in brain, pancreas, olfactory and ocular system development. A requirement for Pax6 in proper formation of lens, iris and retina is well documented. By examining the corneas of heterozygous Small eye (SEY) mice, this report shows that Pax6 is also necessary for normal corneal morphogenesis. In particular, the epithelial component of the postnatal and adult SEY (+/-) cornea is thinner owing to a reduction in the number of cell layers, despite a tenfold increase in the proliferative index and no change in TUNEL labeling. Ultrastructural views revealed large gaps between corneal epithelial cells and a change in the appearance of desmosomes, suggesting that adhesion abnormalities contribute to the corneal phenotype of SEY (+/-) mice. Western blot analysis and immunofluorescence showed equivalent amounts and normal localization of E-cadherin in SEY (+/-) corneas, and the actin cytoskeleton appeared normal as judged by phalloidin staining. By contrast, the levels of desmoglein, β-catenin and γ-catenin were reduced in the SEY (+/-) cornea. In addition, the amount of keratin-12 mRNA and protein, the major intermediate filament, was reduced in SEY (+/-) corneal epithelium as shown by in situ hybridization and immunohistochemistry. Finally, the SEY (+/-) corneal epithelium adheres less well than wild-type when challenged with gentle rubbing using a microsponge. In conclusion, our results indicate that cellular adhesion is compromised in the SEY (+/-) corneal epithelium and suggests a role for Pax6 in the proper generation and maintenance of the adult cornea.

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The metastatic potential of cancer cells is directly attributed to their ability to invade through the extracellular matrix. The mechanisms regulating this cellular invasiveness are poorly understood. Here, we show that junctional adhesion molecule A (JAM-A), a tight junction protein, is a key negative regulator of cell migration and invasion. JAM-A is robustly expressed in normal human mammary epithelium, and its expression is down-regulated in metastatic breast cancer tumors. In breast cancer cell lines, an inverse relationship between JAM-A expression and the ability of these cells to migrate on a collagen matrix was observed, which correlates with the known ability of these cells to metastasize. The T47D and MCF-7 cells, which migrate least, are found to express high levels of JAM-A, whereas the more migratory MDA-MB-468 cells have lower levels of JAM-A on the cell surface. MDA-MB-231 cells, which are highly migratory, express the least amount of JAM-A. Overexpression of JAM-A in MDA-MB-231 cells inhibited both migration and invasion through collagen gels. Furthermore, knockdown of JAM-A using short interfering RNAs enhanced the invasiveness of MDA-MB-231 cells as well as T47D cells. The ability of JAM-A to attenuate cell invasion correlated with the formation of increased numbers of focal adhesions and the formation of functional tight junctions. These results show for the first time that an immunoglobulin superfamily cell adhesion protein expressed at tight junctions could serve as a key negative regulator of breast cancer cell invasion and possibly metastasis. Furthermore, loss of JAM-A could be used as a biomarker for aggressive breast cancer.

Pax6 and c-Maf regulate multiple stages of mammalian lens development. Here, we identified novel distal control regions (DCRs) of the aA-crystallin gene, a marker of lens fiber cell differentiation induced by FGF-signaling. DCR1 stimulated reporter gene expression in primary lens explants treated with FGF2 linking FGF-signaling with aA-crystallin synthesis. A DCR1/aA-crystallin promoter (including DCR2) coupled with EGFP virtually recapitulated the expression pattern of aA-crystallin in lens epithelium and fibers. In contrast, the DCR3/aA/EGFP reporter was expressed only in 'late' lens fibers. Chromatin immunoprecipitations showed binding of Pax6 to DCR1 and the aAcrystallin promoter in lens chromatin and demonstrated that high levels of aA-crystallin expression correlate with increased binding of c-Maf and CREB to the promoter and of CREB to DCR3, a broad domain of histone H3K9-hyperacetylation extending from DCR1 to DCR3, and increased abundance of chromatin remodeling enzymes Brg1 and Snf2h at the aA-crystallin locus. Our data demonstrate a novel mechanism of Pax6, c-Maf and CREB function, through regulation of chromatin-remodeling enzymes, and suggest a multistage model for the activation of aAcrystallin during lens differentiation.