neurogenin3 Is Required for the Development of the Four Endocrine Cell Lineages of the Pancreas

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 4; pp. 1607 - 1611
• Main Authors: Gradwohl, Gérard, Dierich, Andrée, LeMeur, Marianne, Guillemot, François
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 15.02.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors; Biological Sciences; Biology; Cell Differentiation - drug effects; Cell lines; Cellular differentiation; DNA-Binding Proteins - metabolism; Embryonic and Fetal Development; Embryonic stem cells; Endocrine cells; Exocrine cells; Eye Proteins; Genes; Glucagon - metabolism; Helix-Loop-Helix Motifs; Histocytochemistry; Homeodomain Proteins - metabolism; In Situ Hybridization; In Situ Nick-End Labeling; Insulin - metabolism; isl1 gene; Islets of Langerhans; Islets of Langerhans - embryology; Life Sciences; Mice; Mice, Knockout; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural stem cells; neuregenin; NeuroD gene; ngn3 gene; Paired Box Transcription Factors; Pancreas; Pancreas - embryology; Pancreatic cells; pax4 gene; pax6 gene; PAX6 Transcription Factor; Prenatal development; Repressor Proteins; RNA, Messenger - metabolism; Somatostatin - metabolism; Stem cells; Trans-Activators - metabolism; Transcription Factors - metabolism; Xenopus Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.97.4.1607

In the mammalian pancreas, the endocrine cell types of the islets of Langerhans, including the α -,β -,δ -, and pancreatic polypeptide cells as well as the exocrine cells, derive from foregut endodermal progenitors. Recent genetic studies have identified a network of transcription factors, including Pdx1, Isl1, Pax4, Pax6, NeuroD, Nkx2.2, and Hlxb9, regulating the development of islet cells at different stages, but the molecular mechanisms controlling the specification of pancreatic endocrine precursors remain unknown. neurogenin3 (ngn3) is a member of a family of basic helix-loop-helix transcription factors that is involved in the determination of neural precursor cells in the neuroectoderm. ngn3 is expressed in discrete regions of the nervous system and in scattered cells in the embryonic pancreas. We show herein that ngn3-positive cells coexpress neither insulin nor glucagon, suggesting that ngn3 marks early precursors of pancreatic endocrine cells. Mice lacking ngn3 function fail to generate any pancreatic endocrine cells and die postnatally from diabetes. Expression of Isl1, Pax4, Pax6, and NeuroD is lost, and endocrine precursors are lacking in the mutant pancreatic epithelium. Thus, ngn3 is required for the specification of a common precursor for the four pancreatic endocrine cell types.