<i>neurogenin3</i> is required for the development of the four endocrine cell lineages of the pancreas

TLDR

The endocrine cells of the pancreas arise from foregut endodermal progenitors regulated by a network of transcription factors, yet the mechanisms that specify pancreatic endocrine precursors remain unclear, with neurogenin3 (ngn3) a basic helix‑loop‑helix factor expressed in the embryonic pancreas and nervous system. Loss of ngn3 function eliminates all pancreatic endocrine cells, abolishes expression of Isl1, Pax4, Pax6, and NeuroD, and demonstrates that ngn3 is essential for generating a common precursor of the four endocrine lineages.

Abstract

In the mammalian pancreas, the endocrine cell types of the islets of Langerhans, including the alpha-, beta-, delta-, 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.