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Gene Review

Foxf1  -  forkhead box F1

Mus musculus

Synonyms: AI450827, FREAC-1, FREAC1, Fkhl5, Forkhead box protein F1, ...
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Disease relevance of Foxf1a


High impact information on Foxf1a

  • Here, we show that targeting murine Foxf1 and Foxf2, encoding forkhead transcription factors, has pleiotropic effects on intestinal paracrine signaling [1].
  • Foxf expression in the splanchnic mesoderm is activated by Indian and sonic hedgehog secreted by the epithelium [1].
  • Extracellular matrix, particularly collagens, is severely reduced in Foxf mutant intestine, which causes epithelial depolarization and tissue disintegration [1].
  • We found that regenerating Foxf1 +/- liver exhibited defective stellate cell activation following CCl(4) liver injury, which was associated with diminished induction of type I collagen, alpha-smooth muscle actin, and Notch-2 protein and resulted in severe hepatic apoptosis despite normal cellular proliferation rates [4].
  • In conclusion, Foxf1 +/- mice exhibited abnormal liver repair, diminished activation of hepatic stellate cells, and increased pericentral hepatic apoptosis following CCl(4) injury [4].

Chemical compound and disease context of Foxf1a


Biological context of Foxf1a

  • In this study, we show that Foxf1 is expressed in hepatic stellate cells in developing and adult liver, suggesting that a subset of stellate cells originates from septum transversum mesenchyme during mouse embryonic development [4].
  • Foxf1 +/- mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury [4].
  • We have disrupted Foxf1 and show that mutant embryos die at midgestation due to defects in mesodermal differentiation and cell adhesion [6].
  • Expression of Foxf1 and the homeobox gene Irx3 defines the splanchnic and somatic mesodermal layers, respectively [6].
  • Foxf1+/- gall bladders were significantly smaller and had severe structural abnormalities characterized by a deficient external smooth muscle cell layer, reduction in mesenchymal cell number, and in some cases, lack of a discernible biliary epithelial cell layer [7].

Anatomical context of Foxf1a

  • Collectively, our data suggest that sustained expression of Foxf1 is essential for normal lung repair and endothelial cell survival in response to pulmonary cell injury [5].
  • We demonstrate that FoxF2 is expressed in the mesenchyme adjacent to the epithelium in alimentary, respiratory, and urinary tracts, similar to FoxF1 (FREAC-1, HFH-8) [8].
  • In a previous study, we showed that newborn foxf1(+/-) mice with diminished Foxf1 levels exhibited abnormal formation of pulmonary alveoli and capillaries and died postnatally [5].
  • Previous studies have shown that haploinsufficiency of the splanchnic and septum transversum mesoderm Forkhead Box (Fox) f1 transcriptional factor caused defects in lung and gallbladder development and that Foxf1 heterozygous (+/-) mice exhibited defective lung repair in response to injury [4].
  • The forkhead box f1 (Foxf1) transcription factor is expressed in the visceral (splanchnic) mesoderm, which is involved in mesenchymal-epithelial signaling required for development of organs derived from foregut endoderm such as lung, liver, gall bladder, and pancreas [7].

Associations of Foxf1a with chemical compounds


Regulatory relationships of Foxf1a


Other interactions of Foxf1a

  • A possible cause of this is misexpression of the cell-adhesion protein VCAM1 in Foxf1-deficient extra-embryonic mesoderm, which leads to co-expression of VCAM with its receptor, alpha(4)-integrin [6].
  • In contrast, in newborn high-Foxf1(+/-) lungs, Notch-2 signaling was restored to the level found in wild-type mice, which was associated with normal microvascular formation and survival [10].
  • Our previous studies demonstrated that haploinsufficiency of the Foxf1 gene caused pulmonary abnormalities with perinatal lethality from lung hemorrhage in a subset of Foxf1+/- newborn mice [7].

Analytical, diagnostic and therapeutic context of Foxf1a

  • In situ hybridization studies demonstrated that the defective primary lung-bud development in early Foxf1(+/-) embryos was associated with fewer pulmonary mesenchymal-epithelial interfaces [11].


  1. Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production. Ormestad, M., Astorga, J., Landgren, H., Wang, T., Johansson, B.R., Miura, N., Carlsson, P. Development (2006) [Pubmed]
  2. Defects in pulmonary vasculature and perinatal lung hemorrhage in mice heterozygous null for the Forkhead Box f1 transcription factor. Kalinichenko, V.V., Lim, L., Stolz, D.B., Shin, B., Rausa, F.M., Clark, J., Whitsett, J.A., Watkins, S.C., Costa, R.H. Dev. Biol. (2001) [Pubmed]
  3. Differences in the embryonic expression patterns of mouse Foxf1 and -2 match their distinct mutant phenotypes. Ormestad, M., Astorga, J., Carlsson, P. Dev. Dyn. (2004) [Pubmed]
  4. Foxf1 +/- mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury. Kalinichenko, V.V., Bhattacharyya, D., Zhou, Y., Gusarova, G.A., Kim, W., Shin, B., Costa, R.H. Hepatology (2003) [Pubmed]
  5. Wild-type levels of the mouse Forkhead Box f1 gene are essential for lung repair. Kalinichenko, V.V., Zhou, Y., Shin, B., Stolz, D.B., Watkins, S.C., Whitsett, J.A., Costa, R.H. Am. J. Physiol. Lung Cell Mol. Physiol. (2002) [Pubmed]
  6. The forkhead transcription factor Foxf1 is required for differentiation of extra-embryonic and lateral plate mesoderm. Mahlapuu, M., Ormestad, M., Enerbäck, S., Carlsson, P. Development (2001) [Pubmed]
  7. Haploinsufficiency of the mouse Forkhead Box f1 gene causes defects in gall bladder development. Kalinichenko, V.V., Zhou, Y., Bhattacharyya, D., Kim, W., Shin, B., Bambal, K., Costa, R.H. J. Biol. Chem. (2002) [Pubmed]
  8. Forkhead transcription factor FoxF2 is expressed in mesodermal tissues involved in epithelio-mesenchymal interactions. Aitola, M., Carlsson, P., Mahlapuu, M., Enerbäck, S., Pelto-Huikko, M. Dev. Dyn. (2000) [Pubmed]
  9. Differential expression of forkhead box transcription factors following butylated hydroxytoluene lung injury. Kalinichenko, V.V., Lim, L., Shin, B., Costa, R.H. Am. J. Physiol. Lung Cell Mol. Physiol. (2001) [Pubmed]
  10. Foxf1 haploinsufficiency reduces Notch-2 signaling during mouse lung development. Kalinichenko, V.V., Gusarova, G.A., Kim, I.M., Shin, B., Yoder, H.M., Clark, J., Sapozhnikov, A.M., Whitsett, J.A., Costa, R.H. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) [Pubmed]
  11. Fusion of lung lobes and vessels in mouse embryos heterozygous for the forkhead box f1 targeted allele. Lim, L., Kalinichenko, V.V., Whitsett, J.A., Costa, R.H. Am. J. Physiol. Lung Cell Mol. Physiol. (2002) [Pubmed]
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