Myt3 Mediates Laminin-V/Integrin-β1-Induced Islet-Cell Migration via Tgfbi

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 29; no. 9; pp. 1254 - 1268
• Main Authors: Tennant, Bryan R, Chen, Jenny, Shih, Alexis Z. L, Luciani, Dan S, Hoffman, Brad G
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.09.2015; Oxford University Press
• Subjects: Actins - metabolism; Animals; Cadherins - metabolism; Calcium - metabolism; Cell Adhesion - physiology; Cell Adhesion Molecules - metabolism; Cell Movement - physiology; Cell Proliferation - physiology; Cytokines - pharmacology; Extracellular Matrix Proteins - biosynthesis; Extracellular Matrix Proteins - pharmacology; Female; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Integrin beta1 - metabolism; Kalinin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Original Research; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - pharmacology
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/ME.2014-1387

Myt3 is a prosurvival factor in pancreatic islets; however, its role in islet-cell development is not known. Here, we demonstrate that myelin transcription factor 3 (Myt3) is expressed in migrating islet cells in the developing and neonatal pancreas and thus sought to determine whether Myt3 plays a role in this process. Using an ex vivo model of islet-cell migration, we demonstrate that Myt3 suppression significantly inhibits laminin-V/integrin-β1-dependent α- and β-cell migration onto 804G, and impaired 804G-induced F-actin and E-cadherin redistribution. Exposure of islets to proinflammatory cytokines, which suppress Myt3 expression, had a similar effect, whereas Myt3 overexpression partially rescued the migratory ability of the islet cells. We show that loss of islet-cell migration, due to Myt3 suppression or cytokine exposure, is independent of effects on islet-cell survival or proliferation. Myt3 suppression also had no effect on glucose-induced calcium influx, F-actin remodeling or insulin secretion by β-cells. RNA-sequencing (RNA-seq) analysis of transduced islets showed that Myt3 suppression results in the up-regulation of Tgfbi, a secreted diabetogenic factor thought to impair cellular adhesion. Exposure of islets to exogenous transforming growth factor β-induced (Tgfbi) impaired islet-cell migration similar to Myt3 suppression. Taken together, these data suggest a model by which cytokine-induced Myt3 suppression leads to Tgfbi de-repression and subsequently to impaired islet-cell migration, revealing a novel role for Myt3 in regulating islet-cell migration.