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 β1 integrin gene in developing pancreatic β-cells reduces their ability to expand during embryonic life, during the first week of postnatal life, and thereafter. Mice lacking β1 integrin in insulin-producing cells exhibit a dramatic reduction of the number of β-cells to only ∼18% of wild-type levels. Despite the significant reduction in β-cell mass, these mutant mice are not diabetic. A thorough phenotypic analysis of β-cells lacking β1 integrin revealed a normal expression repertoire of β-cell markers, normal architectural organization within islet clusters, and a normal ultrastructure. Global gene expression analysis revealed that ablation of this ECM receptor in β-cells inhibits the expression of genes regulating cell cycle progression. Collectively, our results demonstrate that β1 integrin receptors function as crucial positive regulators of β-cell expansion.
Funding
This work was supported by an American Diabetes Association (ADA) Basic Research Award [1-11-BS-28] and Juvenile Diabetes Research Foundation (JDRF) Research Grants [#1-2005-1084 and #1-2004-13] to V.C.; and by National Institutes of Health grants [RO1 DK55267 to C.J.R., RO1 HL075270 to L.C., P30 DK063491 to G.H.]; G.R.D. was the recipient of a Postdoctoral Fellowship from the JDRF; P.R. was supported by a T32 fellowship [T32 DK007247] from the National Institutes of Health (NIH); and W.Y. by a Pharmacological Sciences Training Grant [5T32GM007750-34] from the NIH and by a scholarship from the Howard Hughes Medical Institute [Med-into-Grad Program #56006778] to the University of Washington. Deposited in PMC for release after 12 months.
Author contributions
G.R.D. performed experiments, analyzed data and contributed to the writing of the manuscript. A.J.J.-C. performed some immunostaining experiments and morphometric analysis. P.R. and W.Y. performed qPCR experiments; G.H. contributed to the analysis of microarray data; C.J.R. contributed to expression profiling analysis of signaling molecules p-ERK1/2, p-AKT, PTEN and α-tubulin. L.C. performed flow cytometry experiments and helped in the analysis of results. V.C. conceived experiments, performed studies of transmission electron microscopy, analyzed data and wrote the manuscript.
