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Gene Review

Foxa1  -  forkhead box A1

Mus musculus

Synonyms: Forkhead box protein A1, HNF-3-alpha, HNF-3A, Hepatocyte nuclear factor 3-alpha, Hnf-3a, ...
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Disease relevance of Foxa1


High impact information on Foxa1

  • Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head [4].
  • Here, we show the mouse Foxa1 expression marks the entire embryonic urogenital sinus epithelium (UGE), contrasting with Shh and Foxa2, which are restricted to the basally located cells during prostate budding [5].
  • Characterization of these mutant cells indicates a population of basal-like cells similar to those found in the embryonic UGE, whereas no differentiated or mature luminal epithelial cells are found in Foxa1-deficient epithelium [5].
  • We have previously shown that a forkhead transcription factor Foxa1 interacts with androgen signaling and controls prostate differentiated response [5].
  • These data indicate that Foxa1 plays a pivotal role in controlling prostate morphogenesis and cell differentiation [5].

Biological context of Foxa1


Anatomical context of Foxa1

  • Members of the Forkhead box a (Foxa) transcription factor family are expressed in the liver, pancreatic islets and intestine and both Foxa1 and Foxa2 regulate proglucagon gene transcription [8].
  • Thus, Foxa1 and Foxa2 are required for the establishment of competence within the foregut endoderm and the onset of hepatogenesis [11].
  • We report here that Foxa2 but not Foxa1 is expressed in the epididymis [12].
  • Thus, we have identified a novel function for Foxa1 in the regulation of oxidative phosphorylation in pancreatic beta-cells [13].
  • This diminished ATP synthesis could be explained by increased expression of the mitochondrial uncoupling protein uncoupling protein 2 (UCP2) in Foxa1-deficient islets, resulting in partially uncoupled mitochondria [13].

Associations of Foxa1 with chemical compounds

  • Intracellular ATP levels after incubation with 10 mmol/l glucose were about 2.5 times lower in Foxa1(-/-) islets compared with controls [13].
  • Moreover, Foxa1(-/-) beta-cells exhibit attenuated calcium influx in response to glucose and glyburide, suggesting an insulin secretion defect either at the level or upstream of the ATP-sensitive K(+) channel [13].
  • Mutations of the human genes encoding the vasopressin 2 receptor and aquaporin 2 cause nephrogenic diabetes insipidus; however, expression of these genes is maintained or increased, respectively, in Foxa1(-/-) mice [2].

Physical interactions of Foxa1

  • Mutational analysis revealed that the homeodomain and Foxa binding sites are each required for activation of the Shh floor plate enhancer, whereas the Tbx site was required for repression in regions of the CNS where Shh is not normally expressed [14].

Regulatory relationships of Foxa1


Other interactions of Foxa1

  • From our results, we conclude that the Adp locus is distinct from either Pax9 or Tcf3a [16].
  • Timing and sites of expression of thyroid transcription factor-1, Foxj1, and beta-tubulin were unaltered in lungs of Foxa1-/- mice [17].
  • Because no evidence for a direct repression of Foxa1 by HNF-6 was found, we postulated the existence of an indirect mechanism [15].
  • Cross-species comparisons narrowed the activity of the Shh floor plate enhancer to an 88-bp sequence within intron 2 of Shh that included highly conserved binding sites matching the consensus for homeodomain, Tbx and Foxa transcription factors [14].
  • Mild nephrogenic diabetes insipidus caused by Foxa1 deficiency [2].

Analytical, diagnostic and therapeutic context of Foxa1


  1. Expression and role of Foxa proteins in prostate cancer. Mirosevich, J., Gao, N., Gupta, A., Shappell, S.B., Jove, R., Matusik, R.J. Prostate (2006) [Pubmed]
  2. Mild nephrogenic diabetes insipidus caused by Foxa1 deficiency. Behr, R., Brestelli, J., Fulmer, J.T., Miyawaki, N., Kleyman, T.R., Kaestner, K.H. J. Biol. Chem. (2004) [Pubmed]
  3. Decreased expression of hepatocyte nuclear factor 3 alpha during the acute-phase response influences transthyretin gene transcription. Qian, X., Samadani, U., Porcella, A., Costa, R.H. Mol. Cell. Biol. (1995) [Pubmed]
  4. Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head. Lai, E., Prezioso, V.R., Tao, W.F., Chen, W.S., Darnell, J.E. Genes Dev. (1991) [Pubmed]
  5. Forkhead box A1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation. Gao, N., Ishii, K., Mirosevich, J., Kuwajima, S., Oppenheimer, S.R., Roberts, R.L., Jiang, M., Yu, X., Shappell, S.B., Caprioli, R.M., Stoffel, M., Hayward, S.W., Matusik, R.J. Development (2005) [Pubmed]
  6. Elevated hepatocyte levels of the Forkhead box A2 (HNF-3beta) transcription factor cause postnatal steatosis and mitochondrial damage. Hughes, D.E., Stolz, D.B., Yu, S., Tan, Y., Reddy, J.K., Watkins, S.C., Diehl, A.M., Costa, R.H. Hepatology (2003) [Pubmed]
  7. Compensatory roles of Foxa1 and Foxa2 during lung morphogenesis. Wan, H., Dingle, S., Xu, Y., Besnard, V., Kaestner, K.H., Ang, S.L., Wert, S., Stahlman, M.T., Whitsett, J.A. J. Biol. Chem. (2005) [Pubmed]
  8. Foxa3 (HNF-3gamma) binds to and activates the rat proglucagon gene promoter but is not essential for proglucagon gene expression. Liu, Y., Shen, W., Brubaker, P.L., Kaestner, K.H., Drucker, D.J. Biochem. J. (2002) [Pubmed]
  9. The role of forkhead box A2 to restrict androgen-regulated gene expression of lipocalin 5 in the mouse epididymis. Yu, X., Suzuki, K., Wang, Y., Gupta, A., Jin, R., Orgebin-Crist, M.C., Matusik, R. Mol. Endocrinol. (2006) [Pubmed]
  10. Foxa3 (hepatocyte nuclear factor 3gamma ) is required for the regulation of hepatic GLUT2 expression and the maintenance of glucose homeostasis during a prolonged fast. Shen, W., Scearce, L.M., Brestelli, J.E., Sund, N.J., Kaestner, K.H. J. Biol. Chem. (2001) [Pubmed]
  11. The initiation of liver development is dependent on Foxa transcription factors. Lee, C.S., Friedman, J.R., Fulmer, J.T., Kaestner, K.H. Nature (2005) [Pubmed]
  12. Foxa1 and foxa2 interact with the androgen receptor to regulate prostate and epididymal genes differentially. Yu, X., Gupta, A., Wang, Y., Suzuki, K., Mirosevich, J., Orgebin-Crist, M.C., Matusik, R.J. Ann. N. Y. Acad. Sci. (2005) [Pubmed]
  13. Foxa1-Deficient Mice Exhibit Impaired Insulin Secretion due to Uncoupled Oxidative Phosphorylation. Vatamaniuk, M.Z., Gupta, R.K., Lantz, K.A., Doliba, N.M., Matschinsky, F.M., Kaestner, K.H. Diabetes (2006) [Pubmed]
  14. Distinct regulators of Shh transcription in the floor plate and notochord indicate separate origins for these tissues in the mouse node. Jeong, Y., Epstein, D.J. Development (2003) [Pubmed]
  15. Transcription factor HNF-6/OC-1 inhibits the stimulation of the HNF-3alpha/Foxa1 gene by TGF-beta in mouse liver. Plumb-Rudewiez, N., Clotman, F., Strick-Marchand, H., Pierreux, C.E., Weiss, M.C., Rousseau, G.G., Lemaigre, F.P. Hepatology (2004) [Pubmed]
  16. Fine genetic mapping defines the genetic order of Pax9, Tcf3a, and Acrodysplasia (Adp). Watanabe, T., Tarttelin, E., Neubüser, A., Kimura, M., Solter, D. Mamm. Genome (1994) [Pubmed]
  17. Stage-specific regulation of respiratory epithelial cell differentiation by Foxa1. Besnard, V., Wert, S.E., Kaestner, K.H., Whitsett, J.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  18. The role of hepatocyte nuclear factor-3 alpha (Forkhead Box A1) and androgen receptor in transcriptional regulation of prostatic genes. Gao, N., Zhang, J., Rao, M.A., Case, T.C., Mirosevich, J., Wang, Y., Jin, R., Gupta, A., Rennie, P.S., Matusik, R.J. Mol. Endocrinol. (2003) [Pubmed]
  19. Characterization of a novel Foxa (hepatocyte nuclear factor-3) site in the glucagon promoter that is conserved between rodents and humans. Sharma, S.K., Leinemann, U., Ratke, R., Oetjen, E., Blume, R., Dickel, C., Knepel, W. Biochem. J. (2005) [Pubmed]
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