Regulation of laminin 1-induced pancreatic beta-cell differentiation by alpha(6) integrin and alpha-dystroglycan
- Author(s)
- Jiang, FX; Georges-Labouesse, E; Harrison, LC;
- Details
- Publication Year 2001-02-01,Volume 7,Issue #2,Page 107-114
- Journal Title
- MOLECULAR MEDICINE
- Publication Type
- Journal Article
- Abstract
- Background: The ability to manipulate the development of pancreatic insulin-producing beta cells has implications for the treatment of type 1 diabetes. Previously, we found that laminin-1, a basement membrane trimeric glycoprotein promotes beta -cell differentiation. We have investigated the mechanism of this effect, using agents that block the receptors for laminin-1, alpha (6) integrin, and alpha -dystroglycan (alpha -DG). Materials and Methods: Dissociated cells from 13.5-day postcoitum (dpc) fetal mouse pancreas were cultured for 4 days with laminin-1, with and without monoclonal antibodies and other agents known to block integrins or alpha -DG. Fetuses fixed in Bouin's solution or fetal pancreas cells fixed in 4% paraformaldehyde were processed for routine histology and for immunohistology to detect hormone expression and bromodeoxyuridine (BrdU) uptake. Results: Blocking the binding of laminin-1 to alpha (6) integrin with a monoclonal antibody, GoH3, abolished cell proliferation (BrdU uptake) and doubled the number of beta cells. Inhibition of molecules involved in alpha (6) integrin signaling (phosphotidylinositol 3-kinase, F-actin, or mitogen-activated protein kinase) had a similar effect. Nevertheless, beta cells appeared to develop normally in alpha (6) integrin-deficient fetuses. Blocking the binding of laminin-1 to alpha -DG with a monoclonal antibody, IIH6, dramatically decreased the number of beta cells. Heparin, also known to inhibit laminin-1 binding to alpha -DG, had a similar effect. In the presence of heparin, the increase in beta cells in response to blocking alpha (6) integrin with GoH3 was abolished. Conclusions: These findings reveal an interplay between alpha (6) integrin and alpha -DG to regulate laminin-1-induced beta -cell development. Laminin-1 had a dominant effect via (U-DG to promote cell survival and beta -cell differentiation, which was modestly inhibited by alpha (6) signaling.
- Publisher
- JOHNS HOPKINS UNIV PRESS
- Keywords
- DYSTROPHIN-GLYCOPROTEIN COMPLEX; IN-VITRO; PHOSPHATIDYLINOSITOL 3-KINASE; EPITHELIAL MORPHOGENESIS; MOLECULAR-ORGANIZATION; EXTRACELLULAR-MATRIX; SIGNAL-TRANSDUCTION; KINASE ACTIVATION; MOUSE; RECEPTOR
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Creation Date: 2001-02-01 12:00:00