Murine Perinatal β-Cell Proliferation and the Differentiation of Human Stem Cell-Derived Insulin-Expressing Cells Require NEUROD1

Diabetes. 2019 Dec;68(12):2259-2271. doi: 10.2337/db19-0117. Epub 2019 Sep 13.

Abstract

Inactivation of the β-cell transcription factor NEUROD1 causes diabetes in mice and humans. In this study, we uncovered novel functions of NEUROD1 during murine islet cell development and during the differentiation of human embryonic stem cells (HESCs) into insulin-producing cells. In mice, we determined that Neurod1 is required for perinatal proliferation of α- and β-cells. Surprisingly, apoptosis only makes a minor contribution to β-cell loss when Neurod1 is deleted. Inactivation of NEUROD1 in HESCs severely impaired their differentiation from pancreatic progenitors into insulin-expressing (HESC-β) cells; however, survival or proliferation was not affected at the time points analyzed. NEUROD1 was also required in HESC-β cells for the full activation of an essential β-cell transcription factor network. These data reveal conserved and distinct functions of NEUROD1 during mouse and human β-cell development and maturation, with important implications about the function of NEUROD1 in diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation / physiology*
  • Cell Line
  • Cell Proliferation / physiology*
  • Cell Survival / physiology
  • Gene Expression Regulation, Developmental
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism*
  • Humans
  • Insulin Secretion / physiology*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • NeuroD protein