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Nkx2.2-repressor activity is sufficient to specify alpha-cells and a small number of beta-cells in the pancreatic islet.

The homeodomain protein Nkx2.2 (Nkx2-2) is a key regulator of pancreatic islet cell specification in mice; Nkx2.2 is essential for the differentiation of all insulin-producing beta-cells and of the majority of glucagon-producing alpha-cells, and, in its absence, these cell types are converted to a ghrelin cell fate. To understand the molecular functions of Nkx2.2 that regulate these early cell-fate decisions during pancreatic islet development, we created Nkx2.2-dominant-derivative transgenic mice. In the absence of endogenous Nkx2.2, the Nkx2.2-Engrailed-repressor derivative is sufficient to fully rescue glucagon-producing alpha-cells and to partially rescue insulin-producing beta-cells. Interestingly, the insulin-positive cells that do form in the rescued mice do not express the mature beta-cell markers MafA or Glut2 (Slc2a2), suggesting that additional activator functions of Nkx2.2 are required for beta-cell maturation. To explore the mechanism by which Nkx2.2 functions as a repressor in the islet, we assessed the pancreatic expression of the Groucho co-repressors, Grg1, Grg2, Grg3 and Grg4 (Tle1-Tle4), which have been shown to interact with and modulate Nkx2.2 function. We determined that Grg3 is highly expressed in the embryonic pancreas in a pattern similar to Nkx2.2. Furthermore, we show that Grg3 physically interacts with Nkx2.2 through its TN domain. These studies suggest that Nkx2.2 functions predominantly as a transcriptional repressor during specification of endocrine cell types in the pancreas.

Pubmed ID: 17202186

Authors

  • Doyle MJ
  • Loomis ZL
  • Sussel L

Journal

Development (Cambridge, England)

Publication Data

February 11, 2007

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P30 DK57516
  • Agency: NIDDK NIH HHS, Id: R01 DK082590
  • Agency: NIGMS NIH HHS, Id: T32-GM08730
  • Agency: NIDDK NIH HHS, Id: U01 DK072504
  • Agency: NIDDK NIH HHS, Id: U01 DK072504-01
  • Agency: NIDDK NIH HHS, Id: U01 DK072504-02
  • Agency: NIDDK NIH HHS, Id: U01 DK072504-03
  • Agency: NIDDK NIH HHS, Id: U01 DK072504-04
  • Agency: NIDDK NIH HHS, Id: U01 DK072504-04S1
  • Agency: NIDDK NIH HHS, Id: U01 DK072504-05
  • Agency: NIDDK NIH HHS, Id: U01 DK072504-05S1
  • Agency: NIDDK NIH HHS, Id: U19 DK061248
  • Agency: NIDDK NIH HHS, Id: U19 DK061248
  • Agency: NIDDK NIH HHS, Id: U19 DK061248-010002
  • Agency: NIDDK NIH HHS, Id: U19 DK061248-020002
  • Agency: NIDDK NIH HHS, Id: U19 DK061248-030002

Mesh Terms

  • Animals
  • Base Sequence
  • Cell Differentiation
  • Co-Repressor Proteins
  • DNA Primers
  • Gene Expression Regulation, Developmental
  • Glucagon-Secreting Cells
  • Homeodomain Proteins
  • Insulin-Secreting Cells
  • Islets of Langerhans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Biological
  • Phenotype
  • Promoter Regions, Genetic
  • Proteins
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors