N-cadherin junction formation drives lens fiber cell differentiation and morphogenesis
Proper establishment and maintenance of lens cytoarchitecture is necessary for lens function. Our studies demonstrate that establishment and maintenance of lens cytoarchitecture are regulated by two distinct populations of N-cadherin junctions; N-cadherin/β-catenin junctions that drive lens fiber cell elongation and establish lens cytoarchitecture through interaction with molecules central to regulation of the actin cytoskeleton, and N-cadherin/γ-catenin junctions that stabilize fiber cell interactions by linking these junctions to the vimentin intermediate filament cytoskeleton. We show that recruitment of α-catenin to N-cadherin/β-catenin junctions is coordinated with the cessation of actin-driven lamellipodial extension, allowing for the close apposition of differentiating lens cell membranes and zipping-up of cell-cell junctions. Maturation of these N-cadherin junctions then leads to recruitment of cortactin and Arp3, which can nucleate the actin filament assembly necessary for extension of cell-cell contact zones and generation of forces that drive fiber cell elongation. Src family kinases (SFKs) have a biphasic role in lens cell differentiation related to their function at N-cadherin junctions. c-Src, which links directly to N-cadherin junctions and keeps them in a nascent form, is responsible for maintaining lens epithelial cells in their proliferative, undifferentiated state. In contrast, the SFK Fyn, recruited to and activated in the N-cadherin complex, provides a signal necessary for lens fiber cell differentiation and morphogenesis. Cadherin activation of Fyn has been shown to activate the PI3K/Rac signaling pathway, and Rac activates cortactin/Arp2/3 to drives actin polymerization. Therefore, we propose that actin assembly that drives lens fiber cell elongation is likely initiated by an N-cadherin/fyn/cortactin/Arp3 pathway. While N-cadherin/β-catenin junctions drive lens fiber cell morphogenesis and the establishment of lens cytoarchitecture, N-cadherin/γ-catenin junctions are involved in the maintenance of lens cytoarchitecture. We identified a new, vimentin intermediate filament-linked N-cadherin junction in differentiating lens fiber cells. Using a novel double immunoprecipitation technique that allowed for the biochemical separation of N-cadherin/β-catenin and N-cadherin/γ-catenin junctions, we demonstrated that, similar to desmosomal cadherins, this N-cadherin intermediate filament linkage is specific to γ-catenin-containing junctions and is mediated by the linker protein desmoplakin. The vimentin-linked N-cadherin/γ-catenin junction is likely critical for stabilizing lens cytoarchitecture established by N-cadherin/β-catenin-directed actin assembly and organization.
Leonard, Michelle, "N-cadherin junction formation drives lens fiber cell differentiation and morphogenesis" (2008). ETD Collection for Thomas Jefferson University. AAI3420050.