β1 integrin is a crucial regulator of pancreatic β-cell expansion

Development of the endocrine compartment of the pancreas, as represented by the islets of Langerhans, occurs through a series of highly regulated events encompassing branching of the pancreatic epithelium, delamination and differentiation of islet progenitors from ductal domains, followed by expansion and three-dimensional organization into islet clusters. Cellular interactions with the extracellular matrix (ECM) mediated by receptors of the integrin family are postulated to regulate key functions in these processes. Yet, specific events regulated by these receptors in the developing pancreas remain unknown. Here, we show that ablation of the beta 1 integrin gene in developing pancreatic beta-cells reduces their ability to expand during embryonic life, during the first week of postnatal life, and thereafter. Mice lacking beta 1 integrin in insulin-producing cells exhibit a dramatic reduction of the number of beta-cells to only similar to 18% of wild-type levels. Despite the significant reduction in beta-cell mass, these mutant mice are not diabetic. A thorough phenotypic analysis of beta-cells lacking beta 1 integrin revealed a normal expression repertoire of beta-cell markers, normal architectural organization within islet clusters, and a normal ultrastructure. Global gene expression analysis revealed that ablation of this ECM receptor in beta-cells inhibits the expression of genes regulating cell cycle progression. Collectively, our results demonstrate that beta 1 integrin receptors function as crucial positive regulators of beta-cell expansion.