β1‐integrin controls cell fate specification in early lens development

Abstract

Integrins are heterodimeric cell surface molecules that mediate cell-extracellular matrix (ECM) adhesion, ECM assembly, and regulation of both ECM and growth factor induced signaling. However, the developmental context of these diverse functions is not clear. Loss of β1-integrin from the lens vesicle (mouse E10.5) results in abnormal exit of anterior lens epithelial cells (LECs) from the cell cycle and their aberrant elongation toward the presumptive cornea by E12.5. These cells lose expression of LEC markers and initiate expression of the Maf (also known as c-Maf) and Prox1 transcription factors as well as other lens fiber cell markers, β1-integrin null LECs also upregulate the ERK, AKT and Smad1/5/8 phosphorylation indicative of BMP and FGF signaling. By E14.5, β1-integrin null lenses have undergone a complete conversion of all lens epithelial cells into fiber cells. These data suggest that shortly after lens vesicle closure, β1-integrin blocks inappropriate differentiation of the lens epithelium into fibers, potentially by inhibiting BMP and/or FGF receptor activation. Thus, β1-integrin has an important role in fine-tuning the response of the early lens to the gradient of growth factors that regulate lens fiber cell differentiation.

The occhiolino (occ) mutant Zebrafish, a model for development of the optical function in the biological lens

“…Laminin mutants disrupt basement membrane structure, resulting in abnormal lens development in Zebrafish as early as 3 dpf, with some mutations causing complete loss of the lens as early at 7 dpf (Parmigiani and McAvoy, ; Semina et al, ; Zinkevich et al, ; Pathania et al, ; Patel et al, ). The involvement of laminin in the formation of the basement membrane was the basis for using laminin antibodies to label the lens capsule in wt and occ eyes (Pathania et al, ; Pathania et al, ). A number of studies on recessive laminin mutations in Zebrafish established the significance of the lens basement membrane in normal development and found that the impact of a laminin mutation is not limited to the eye but often has a dramatic systemic phenotype.…”

“…The most prominent constituent of basement membranes is type IV collagen, which has a diverse and multifunctional involvement in normal cell differentiation and in human diseases of the kidney, vasculature, tumors, and sensory systems, including the eye (Norose et al, 2000;Dong et al, 2002;Cvekl and Duncan, 2007;Kwan, 2014;Pathania et al, 2016). Although laminin is well established as an immunohistochemical marker for the basement membrane, mutations in laminin produce more severe phenotypes than those observed in the occ Zebrafish.…”

Signaling and Gene Regulatory Networks in Mammalian Lens Development

“…Integrins are the major adhesion receptors at the basal side of the lens cells, connecting the internal cytoskeleton to the extracellular matrix in the lens capsule. In the lens epithelium, the cell differentiation program is suppressed by β1-integrin that antagonizes FGF signaling, but promoted by α6-integrin that activates IGF signaling [229, 230]. Although the exact mechanism for such divergent roles of integrins is not clear, genetic evidence supports the model that integrin signaling is regulated by the transmembrane protein Crim1, mediated by the pseudokinase ILK and ultimately conveyed to small GTPases such as Rac and Rap to control cell adhesion and basement membrane assembly [231–235].…”

β1-Integrin Deletion From the Lens Activates Cellular Stress Responses Leading to Apoptosis and Fibrosis

“… 10 , 11 They are best known as mediators of bidirectional cell communication with the extracellular matrix and cell surface proteins on neighboring cells. 10 , 12 The ocular lens expresses β1-integrins in all cells, 13 – 15 and these proteins are proposed to be major regulators of lens cell contact with their basement membrane (the lens capsule) due to their localization at the basal surface of all lens cells. 16 – 18 This is consistent with the significant transcript-level expression, in the embryonic day (E)15.5 mouse lens, of several α-integrins that are capable of forming extracellular matrix–binding αβ1 heterodimers.…”

“… 19 Of these, α6β1 and α3β1 are likely to be the functionally most crucial in the lens, as α6/α3-integrin double-null lenses exhibit abnormalities similar to those arising from β1-integrin deletion from the early lens. 15 , 20 However, no one α-integrin is likely responsible for all lens integrin functions, as suggested by the findings that α6-integrin null lenses exhibit only mild defects, 20 , 21 whereas α3-integrin 20 and αV-integrin null 22 lenses are morphologically indistinguishable from wild type (WT). Lens integrins also likely regulate growth factor signaling by diverse mechanisms, such as the activation of latent growth factors 22 or direct binding to growth factor receptors in cis , 15 , 23 , 24 as well as indirectly via integrin-mediated signal transduction.…”