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Gene Review

Foxa2  -  forkhead box A2

Mus musculus

Synonyms: Forkhead box protein A2, HNF-3-beta, HNF-3B, HNF3-beta, HNF3beta, ...
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Disease relevance of Foxa2

  • In particular, Foxa2 may be involved in progression of prostate cancer to androgen independence [1].
  • Prominent Foxa1 and Foxa2 expression was observed in 12T-10 invasive undifferentiated neuroendocrine carcinomas, in the hormone independent and metastasizing 12T-10 derived, NE-10 allograft tumors, and in all metastatic lesions isolated from 12T-10 mice [1].
  • Foxa1 protein expression was always observed in human prostate carcinomas, regardless of Gleason grade score, while Foxa2 was only detected in neuroendocrine small cell carcinomas and in some high Gleason score adenocarcinomas [1].
  • We have identified the two subunits of the beta-cell ATP-sensitive K(+) channel (K(ATP)), the most frequently mutated genes linked to familial hyperinsulinism, as novel Foxa2 targets in islets [2].
  • Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia [2].

High impact information on Foxa2


Chemical compound and disease context of Foxa2


Biological context of Foxa2


Anatomical context of Foxa2

  • Mice hypomorphic for Tbx1 failed to activate expression of the forkhead transcription factor Foxa2 in the pharyngeal mesoderm, which contains cardiac outflow precursors derived from the anterior heart field [14].
  • These phenotypic changes are accompanied with molecular aberrations, including focal epithelial activation of Shh and elevated Foxa2 and Notch1 in the null epithelium [15].
  • Accordingly, the promoter domain containing HF1 and HF2 is recognized by cerebellum nuclear extracts containing Engrailed and Foxa2 and has regulatory functions in primary cultures of embryonic mesmetencephalic nerve cells [16].
  • Foxa1 and Foxa2 are closely related family members of the Foxa group of transcription factors that are coexpressed in subsets of respiratory epithelial cells throughout lung morphogenesis [10].
  • Here, we report that Foxa2 displays a region-specific expression pattern along the epididymis: no staining observed in initial segment, light staining in proximal caput, gradiently heavier staining in middle and distal caput, and strongest staining in corpus and cauda, regions with little or no expression of Lcn5 [11].

Associations of Foxa2 with chemical compounds


Physical interactions of Foxa2


Co-localisations of Foxa2


Regulatory relationships of Foxa2

  • These results suggest that Tead activates the Foxa2 enhancer core element in the mouse node in cooperation with a second factor that binds to the 5' element, and that a similar mechanism also operates in the zebrafish shield [23].
  • In preadipocytes Foxa-2 inhibits adipocyte differentiation by activating transcription of the Pref-1 gene [24].
  • We conclude that glucagon gene expression may be regulated by the relative abundance of the three different HNF-3 beta variants in alpha-cells [25].
  • In vitro, both wild type and activated beta-catenin negatively regulated the expression of the Foxa2 promoter [26].
  • In support of the role of HNF-6 in regulating HNF-3beta expression in developing hepatocytes, their liver expression levels are both transiently reduced between 14 and 15 days of gestation [27].

Other interactions of Foxa2

  • 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 [15].
  • At 11.5 days p.c., hepatocyte nuclear factor-3beta (Hnf-3beta) is expressed uniformly throughout the epithelium, while Wnt-2 expression is confined to the distal mesenchyme [28].
  • Genes normally transcribed in organizer-derived tissues, such as Gsc and Foxa2, are also expressed in Nodal-/- epiblast [29].
  • Also, expression of Foxa2 across the dorsoventral axis of the endoderm is not affected in Raldh2-/- embryos, indicating that a lack of RA does not cause a general defect in foregut endoderm development [30].
  • Within the caudal notochord, developing floorplate, and hindgut, HNF3alpha, HNF3beta, Shh, and Brachyury expression domains correlate directly with known genetic roles and predicted tissue interdependence during induction and differentiation of these structures [31].

Analytical, diagnostic and therapeutic context of Foxa2

  • RT-PCR analysis identified low Foxa2 mRNA expression levels in the ventral and dorsolateral lobes of the adult prostate, with Foxa2 epithelial cell expression being localized to periurethral regions of the murine adult prostatic complex [32].
  • Hadhsc is a direct target of Foxa2, as demonstrated by cotransfection as well as in vivo chromatin immunoprecipitation experiments using isolated islets [33].
  • RNA microarray analysis at embryonic day 18.5 demonstrated that Foxa2-regulated expression of a group of genes mediating surfactant protein and lipid synthesis, host defense, and antioxidant production [34].
  • We also examined the mRNA levels of HNF6 targets in the liver using a cDNA array and found that their expression was similar in Foxa2-deficient and control mice [20].
  • Electrophoretic mobility shift assays showed that TTF-1, GATA6, and Foxa2 can bind to a specific subset of their consensus DNA binding sites within the WNT7b promoter [35].


  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. Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia. Sund, N.J., Vatamaniuk, M.Z., Casey, M., Ang, S.L., Magnuson, M.A., Stoffers, D.A., Matschinsky, F.M., Kaestner, K.H. Genes Dev. (2001) [Pubmed]
  3. HNF-3 beta as a regulator of floor plate development. Sasaki, H., Hogan, B.L. Cell (1994) [Pubmed]
  4. HNF-3 beta is essential for node and notochord formation in mouse development. Ang, S.L., Rossant, J. Cell (1994) [Pubmed]
  5. The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo. Weinstein, D.C., Ruiz i Altaba, A., Chen, W.S., Hoodless, P., Prezioso, V.R., Jessell, T.M., Darnell, J.E. Cell (1994) [Pubmed]
  6. Coactivation of Foxa2 through Pgc-1beta promotes liver fatty acid oxidation and triglyceride/VLDL secretion. Wolfrum, C., Stoffel, M. Cell metabolism. (2006) [Pubmed]
  7. Delayed activation of HNF-3 beta upon retinoic acid-induced teratocarcinoma cell differentiation. Reichel, R.R., Budhiraja, S., Jacob, A. Exp. Cell Res. (1994) [Pubmed]
  8. Association between hepatocyte nuclear factor 6 (HNF-6) and FoxA2 DNA binding domains stimulates FoxA2 transcriptional activity but inhibits HNF-6 DNA binding. Rausa, F.M., Tan, Y., Costa, R.H. Mol. Cell. Biol. (2003) [Pubmed]
  9. 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]
  10. 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]
  11. 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]
  12. A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. Sasaki, H., Hui, C., Nakafuku, M., Kondoh, H. Development (1997) [Pubmed]
  13. FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse. Hoodless, P.A., Pye, M., Chazaud, C., Labbé, E., Attisano, L., Rossant, J., Wrana, J.L. Genes Dev. (2001) [Pubmed]
  14. Tbx1 regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors. Hu, T., Yamagishi, H., Maeda, J., McAnally, J., Yamagishi, C., Srivastava, D. Development (2004) [Pubmed]
  15. 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]
  16. Joint regulation of the MAP1B promoter by HNF3beta/Foxa2 and Engrailed is the result of a highly conserved mechanism for direct interaction of homeoproteins and Fox transcription factors. Foucher, I., Montesinos, M.L., Volovitch, M., Prochiantz, A., Trembleau, A. Development (2003) [Pubmed]
  17. Foxa2 integrates the transcriptional response of the hepatocyte to fasting. Zhang, L., Rubins, N.E., Ahima, R.S., Greenbaum, L.E., Kaestner, K.H. Cell metabolism. (2005) [Pubmed]
  18. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. Ha, E., Yim, S.V., Chung, J.H., Yoon, K.S., Kang, I., Cho, Y.H., Baik, H.H. J. Pineal Res. (2006) [Pubmed]
  19. Foxa2 controls vesicle docking and insulin secretion in mature Beta cells. Gao, N., White, P., Doliba, N., Golson, M.L., Matschinsky, F.M., Kaestner, K.H. Cell Metab. (2007) [Pubmed]
  20. Transcriptional networks in the liver: hepatocyte nuclear factor 6 function is largely independent of Foxa2. Rubins, N.E., Friedman, J.R., Le, P.P., Zhang, L., Brestelli, J., Kaestner, K.H. Mol. Cell. Biol. (2005) [Pubmed]
  21. Identification of a transthyretin enhancer site that selectively binds the hepatocyte nuclear factor-3 beta isoform. Samadani, U., Qian, X., Costa, R.H. Gene Expr. (1996) [Pubmed]
  22. Atypical mouse cerebellar development is caused by ectopic expression of the forkhead box transcription factor HNF-3beta. Zhou, H., Hughes, D.E., Major, M.L., Yoo, K., Pesold, C., Costa, R.H. Gene Expr. (2001) [Pubmed]
  23. Tead proteins activate the Foxa2 enhancer in the node in cooperation with a second factor. Sawada, A., Nishizaki, Y., Sato, H., Yada, Y., Nakayama, R., Yamamoto, S., Nishioka, N., Kondoh, H., Sasaki, H. Development (2005) [Pubmed]
  24. Role of Foxa-2 in adipocyte metabolism and differentiation. Wolfrum, C., Shih, D.Q., Kuwajima, S., Norris, A.W., Kahn, C.R., Stoffel, M. J. Clin. Invest. (2003) [Pubmed]
  25. Hepatocyte-nuclear factor 3 beta gene transcripts generate protein isoforms with different transactivation properties on the glucagon gene. Philippe, J. Mol. Endocrinol. (1995) [Pubmed]
  26. Beta-catenin regulates differentiation of respiratory epithelial cells in vivo. Mucenski, M.L., Nation, J.M., Thitoff, A.R., Besnard, V., Xu, Y., Wert, S.E., Harada, N., Taketo, M.M., Stahlman, M.T., Whitsett, J.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  27. In situ hybridization with 33P-labeled RNA probes for determination of cellular expression patterns of liver transcription factors in mouse embryos. Rausa, F.M., Ye, H., Lim, L., Duncan, S.A., Costa, R.H. Methods (1998) [Pubmed]
  28. Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis. Bellusci, S., Henderson, R., Winnier, G., Oikawa, T., Hogan, B.L. Development (1996) [Pubmed]
  29. Absence of Nodal signaling promotes precocious neural differentiation in the mouse embryo. Camus, A., Perea-Gomez, A., Moreau, A., Collignon, J. Dev. Biol. (2006) [Pubmed]
  30. Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development. Molotkov, A., Molotkova, N., Duester, G. Dev. Dyn. (2005) [Pubmed]
  31. Genetic patterning of the developing mouse tail at the time of posterior neuropore closure. Gofflot, F., Hall, M., Morriss-Kay, G.M. Dev. Dyn. (1997) [Pubmed]
  32. Expression of Foxa transcription factors in the developing and adult murine prostate. Mirosevich, J., Gao, N., Matusik, R.J. Prostate (2005) [Pubmed]
  33. Foxa2 regulates multiple pathways of insulin secretion. Lantz, K.A., Vatamaniuk, M.Z., Brestelli, J.E., Friedman, J.R., Matschinsky, F.M., Kaestner, K.H. J. Clin. Invest. (2004) [Pubmed]
  34. Foxa2 is required for transition to air breathing at birth. Wan, H., Xu, Y., Ikegami, M., Stahlman, M.T., Kaestner, K.H., Ang, S.L., Whitsett, J.A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  35. The WNT7b promoter is regulated by TTF-1, GATA6, and Foxa2 in lung epithelium. Weidenfeld, J., Shu, W., Zhang, L., Millar, S.E., Morrisey, E.E. J. Biol. Chem. (2002) [Pubmed]
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