title: G protein-coupled receptor signaling and sphingosine-1-phosphate play a phylogenetically conserved role in endocrine pancreas morphogenesis.
abstract: During development pancreatic endocrine cells migrate in a coordinated fashion. This migration is necessary to form fully functional islets, but the mechanisms involved remain unknown. Therapeutic strategies to restore β-cell mass and islet functionality by reprogramming endogenous exocrine cells would be strengthened from simultaneous treatments that enhance endocrine cell clustering. We found that endocrine progenitors respond to and regulate G protein-coupled receptor (GPCR) signaling in order to cluster in islets. Rgs4, a dedicated regulator of GPCR signaling, was specifically expressed in early epithelial endocrine progenitors of both zebrafish and mouse, and its expression in the mouse endocrine progenitors was strictly dependent upon Ngn3, the key specification gene of the endocrine lineage. Rgs4 loss of function resulted in defects in islet cell aggregation. By genetically inactivating Gα(i)-mediated GPCR signaling in endocrine progenitors, we established its role in islet cell aggregation in both mouse and zebrafish. Finally, we identified sphingosine-1-phosphate (S1P) as a ligand mediating islet cell aggregation in both species acting through distinct but closely related receptors.
authors.affiliation: Developmental Biology Laboratory, Biomedical Research Foundation of the Academy of Athens, Soranou Ephessiou 4, Athens 11527, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Serafimidis
authors.forename: Scott
authors.initials: S
authors.lastname: Heximer
authors.forename: Dimitris
authors.initials: D
authors.lastname: Beis
authors.forename: Anthony
authors.initials: A
authors.lastname: Gavalas
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D007515:Islets of Langerhans / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D010802:Phylogeny; D020710:RGS Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D008246:Lysophospholipids; D009419:Nerve Tissue Proteins; D020710:RGS Proteins; D043562:Receptors, G-Protein-Coupled; D013110:Sphingosine; C407737:Neurog3 protein, mouse; C098799:RGS4 protein; C060506:sphingosine 1-phosphate