Foxa2 is required for the differentiation of pancreatic alpha-cells.
The differentiation of insulin-producing beta-cells has been investigated in great detail; however, little is known about the factors that delineate the second-most abundant endocrine lineage, the glucagon-producing alpha-cell. Here we utilize a novel YAC-based Foxa3Cre transgene to delete the winged helix transcription factor Foxa2 (formerly HNF-3beta) in the pancreatic primordium during midgestation. The resulting Foxa2(loxP/loxP); Foxa3Cre mice are severely hypoglycemic and die within the first week of life. Mutant mice are hypoglucagonemic secondary to a 90% reduction of glucagon expression. While the number of mature glucagon-positive alpha-cells is dramatically reduced, specification of alpha-cell progenitors is not affected by Foxa2 deficiency. By marker gene analysis, we show that the expression of the alpha-cell transcription factors Arx, Pax6, and Brn4 does not require Foxa2 in the transcriptional hierarchy governing alpha-cell differentiation.
Lee
Catherine S
CS
Department of Genetics and Penn Diabetes Center, University of Pennsylvania School of Medicine, 415 Curie Boulevard, CRB 560 Philadelphia, PA 19104, USA.
Sund
Newman J
NJ
Behr
Rüdiger
R
Herrera
Pedro L
PL
Kaestner
Klaus H
KH
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D018244:Chromosomes, Artificial, Yeast; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D051542:Hepatocyte Nuclear Factor 3-beta; D007003:Hypoglycemia / Q000235:genetics; D007515:Islets of Langerhans / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D010179:Pancreas / Q000196:embryology*; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; C496503:Foxa2 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta