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Nkx22-repressor activity is sufficient t ... a-cells in the pancreatic islet
Nkx22-repressor activity is sufficient to specify alpha-cells and a small number of beta-cells in the pancreatic islet
5441
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.
Doyle MJ, Loomis ZL, Sussel L
Development (Cambridge, England)
2007-02-01 00:00
134
3
515-23
Animals,Base Sequence,Cell Differentiation,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 (Genetics),Proteins,Repressor Proteins,Trans-Activators,Transcription Factors,DNA Primers,Homeodomain Proteins,Nkx-2.2 homedomain protein,Proteins,Repressor Proteins,Tle3 protein, mouse,Trans-Activators,Transcription Factors,insulin promoter factor 1
Program in Molecular Biology, University of Colorado at Denver Health Sciences Center, Aurora, CO 80045, USA.
Development
NIDDK P30 DK57516, NIGMS T32-GM08730, NIDDK U19 DK061248
0950-1991
10.1242/dev.02763
dev.02763
0
False
17202186
