title: β1 integrin is a crucial regulator of pancreatic β-cell expansion.
abstract: 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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16 20139, Milan, Italy.
authors.forename: Giuseppe R
authors.initials: GR
authors.lastname: Diaferia
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Jimenez-Caliani
authors.forename: Prerana
authors.initials: P
authors.lastname: Ranjitkar
authors.forename: Wendy
authors.initials: W
authors.lastname: Yang
authors.forename: Gary
authors.initials: G
authors.lastname: Hardiman
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rhodes
authors.forename: Laura
authors.initials: L
authors.lastname: Crisa
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cirulli
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002452:Cell Count; D002453:Cell Cycle; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D048430:Cell Shape; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000648:ultrastructure; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic
chemical_list: D007328:Insulin; D019012:Integrin beta1; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Cell adhesion; Extracellular matrix; Islets of Langerhans; Mouse; Proliferation; β-cell development; β1 integrin