Winged-helix transcription factors and pancreatic development.
The forkhead gene family, named after the founding gene member in Drosophila, is characterized by a unique DNA-binding domain. This so-called forkhead box encodes a winged-helix DNA-binding motif, the name of which describes the structure of the domain when bound to DNA. The three Fox (forkhead box) group A genes, Foxa1, Foxa2 and Foxa3, are expressed in embryonic endoderm, the germ layer that gives rise to the digestive system, and contribute to the specification of the pancreas and the regulation of glucose homoeostasis. Deletion of the Foxa2 gene in pancreatic beta-cells in mice results in a phenotype resembling PHHI (persistent hyperinsulinaemic hypoglycaemia of infancy). Molecular analyses have demonstrated that Foxa2 is an important regulator of the genes encoding Sur1, Kir6.2 and Schad (short chain L-3-hydroxyacyl-CoA dehydrogenase), mutation of which causes PHHI in humans. Foxa1 was shown to be an essential activator of glucagon gene expression in vivo. An additional winged-helix protein, Foxo1, contributes to pancreatic beta-cell function by regulating the Pdx1 gene, which is required for pancreatic development in cooperation with Foxa2.
Lantz
Kristen A
KA
Department of Genetics, University of Pennsylvania Medical School, 560 Clinical Research Building, 415 Curie Blvd, Philadelphia, PA 19104, USA.
Kaestner
Klaus H
KH
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D003920:Diabetes Mellitus / Q000196:embryology / Q000378:metabolism; D047108:Embryonic Development / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D051542:Hepatocyte Nuclear Factor 3-beta; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008322:Mammals / Q000196:embryology*; D051379:Mice; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D010179:Pancreas / Q000196:embryology*; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; C496502:FOXA2 protein, human; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C496503:Foxa2 protein, mouse; C496504:Foxa2 protein, rat; D018398:Homeodomain Proteins; C114562:LUN protein, vertebrate; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D051542:Hepatocyte Nuclear Factor 3-beta; C074639:Foxo1 protein, rat