title: Myt3 Mediates Laminin-V/Integrin-β1-Induced Islet-Cell Migration via Tgfbi.
abstract: 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.
authors.affiliation: Child and Family Research Institute (B.R.T., J.C., A.Z.L.S., D.S.L., B.G.H.), British Columbia Children's Hospital and Sunny Hill Health Centre, Vancouver, British Columbia, Canada V5Z 4H4; and Department of Surgery (D.S.L., B.G.H.), University of British Columbia, Vancouver, British Columbia, Canada V5Z 4E3.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Tennant
authors.affiliation: Child and Family Research Institute (B.R.T., J.C., A.Z.L.S., D.S.L., B.G.H.), British Columbia Children's Hospital and Sunny Hill Health Centre, Vancouver, British Columbia, Canada V5Z 4H4; and Department of Surgery (D.S.L., B.G.H.), University of British Columbia, Vancouver, British Columbia, Canada V5Z 4E3.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chen
authors.affiliation: Child and Family Research Institute (B.R.T., J.C., A.Z.L.S., D.S.L., B.G.H.), British Columbia Children's Hospital and Sunny Hill Health Centre, Vancouver, British Columbia, Canada V5Z 4H4; and Department of Surgery (D.S.L., B.G.H.), University of British Columbia, Vancouver, British Columbia, Canada V5Z 4E3.
authors.forename: Alexis Z L
authors.initials: AZ
authors.lastname: Shih
authors.affiliation: Child and Family Research Institute (B.R.T., J.C., A.Z.L.S., D.S.L., B.G.H.), British Columbia Children's Hospital and Sunny Hill Health Centre, Vancouver, British Columbia, Canada V5Z 4H4; and Department of Surgery (D.S.L., B.G.H.), University of British Columbia, Vancouver, British Columbia, Canada V5Z 4E3.
authors.forename: Dan S
authors.initials: DS
authors.lastname: Luciani
authors.affiliation: Child and Family Research Institute (B.R.T., J.C., A.Z.L.S., D.S.L., B.G.H.), British Columbia Children's Hospital and Sunny Hill Health Centre, Vancouver, British Columbia, Canada V5Z 4H4; and Department of Surgery (D.S.L., B.G.H.), University of British Columbia, Vancouver, British Columbia, Canada V5Z 4E3.
authors.forename: Brad G
authors.initials: BG
authors.lastname: Hoffman
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000494:pharmacology; D005260:Female; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology; D000097794:Kalinin; D000099222:betaIG-H3 Protein
chemical_list: D000199:Actins; D015820:Cadherins; D002118:Calcium; D015815:Cell Adhesion Molecules; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D007328:Insulin; D019012:Integrin beta1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000097794:Kalinin; D000099222:betaIG-H3 Protein; C581556:Myt3 protein, mouse