Genetic identification of a novel NeuroD1 function in the early differentiation of islet alpha, PP and epsilon cells

Dev Biol. 2007 Dec 15;312(2):523-32. doi: 10.1016/j.ydbio.2007.09.057. Epub 2007 Oct 5.


Nkx2.2 and NeuroD1 are vital for proper differentiation of pancreatic islet cell types. Nkx2.2-null mice fail to form beta cells, have reduced numbers of alpha and PP cells and display an increase in ghrelin-producing epsilon cells. NeuroD1-null mice display a reduction of alpha and beta cells after embryonic day (e) 17.5. To begin to determine the relative contributions of Nkx2.2 and NeuroD1 in islet development, we generated Nkx2.2-/-;NeuroD1-/- double knockout (DKO) mice. As expected, the DKO mice fail to form beta cells, similar to the Nkx2.2-null mice, suggesting that the Nkx2.2 phenotype may be dominant over the NeuroD1 phenotype in the beta cells. Surprisingly, however, the alpha, PP and epsilon phenotypes of the Nkx2.2-null mice are partially rescued by the simultaneous elimination of NeuroD1, even at early developmental time points when NeuroD1 null mice alone do not display a phenotype. Our results indicate that Nkx2.2 and NeuroD1 interact to regulate pancreatic islet cell fates, and this epistatic relationship is cell-type dependent. Furthermore, this study reveals a previously unappreciated early function of NeuroD1 in regulating the specification of alpha, PP and epsilon cells.

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 / physiology*
  • Cell Differentiation / genetics
  • Embryo, Mammalian / metabolism
  • Gene Expression Regulation, Developmental
  • Ghrelin / biosynthesis
  • Glucagon / biosynthesis
  • Glucagon-Secreting Cells / metabolism*
  • Homeobox Protein Nkx-2.2
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Islets of Langerhans / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • POU Domain Factors / metabolism
  • Pancreatic Polypeptide-Secreting Cells / metabolism*
  • Phenotype
  • RNA, Messenger / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Zebrafish Proteins


  • Basic Helix-Loop-Helix Transcription Factors
  • Ghrelin
  • Homeobox Protein Nkx-2.2
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Neurod1 protein, mouse
  • Nkx2-2 protein, mouse
  • POU Domain Factors
  • RNA, Messenger
  • Transcription Factors
  • Zebrafish Proteins
  • nkx2.2b protein, zebrafish
  • Pou3f4 protein, mouse
  • Glucagon