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Gene Review

Foxc1  -  forkhead box C1

Mus musculus

Synonyms: FREAC-3, FREAC3, Fkh1, Fkhl7, Forkhead box protein C1, ...
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Disease relevance of Foxc1

  • Foxc1/Mf1 is disrupted in the mutant, congenital hydrocephalus (Foxc1/Mf1(ch)), which has multiple developmental defects [1].
  • Here, we show that mouse embryos compound mutant for Foxc1 and Foxc2, two closely related Fox transcription factors, exhibit arteriovenous malformations and lack of induction of arterial markers whereas venous markers such as COUP-TFII are normally expressed, suggesting that mutant endothelial cells fail to acquire an arterial fate [2].
  • Expression of the Mf1 gene in developing mouse hearts: implication in the development of human congenital heart defects [3].
  • To this end, high-dose attenuated VSV-G pseudotyped equine infectious anaemia virus (EIAV) encoding beta-galactosidase under the CMV promoter was injected into the fetal circulation of immuno-competent MF1 mice [4].
  • We report here that recombinant retrovirus producing cells administered into the intra-amniotic cavity of mid- to late-gestation mouse MF1 foetuses survive in the amniotic fluid and are able to engraft to a certain extent in foetal tissues [5].

Psychiatry related information on Foxc1


High impact information on Foxc1

  • We show that a commercially available strain of outbred mice, MF1, can be treated as an ultrafine mosaic of standard inbred strains and accordingly used to dissect a known quantitative trait locus influencing anxiety [7].
  • Mf1 encodes a forkhead/winged helix transcription factor expressed in many embryonic tissues, including prechondrogenic mesenchyme, periocular mesenchyme, meninges, endothelial cells, and kidney [8].
  • The human Mf1 homolog FREAC3 is a candidate gene for ocular dysgenesis and glaucoma mapping to chromosome 6p25-pter, and deletions of this region are associated with multiple developmental disorders, including hydrocephaly and eye defects [8].
  • We show that congenital hydrocephalus involves a point mutation in Mf1, generating a truncated protein lacking the DNA-binding domain [8].
  • Mutant fetuses are retarded in growth and die at mid-gestation in a 129/Sv genetic background, whereas in a 129/Sv x C57BL/6 cross some survive until birth and even to postnatal day 20 in a 129/Sv x C57BL/6 x MF1 background [9].

Chemical compound and disease context of Foxc1


Biological context of Foxc1


Anatomical context of Foxc1

  • We show here that, depending on the genetic background, most Foxc1 homozygous mutants are born with abnormalities of the metanephric kidney, including duplex kidneys and double ureters, one of which is a hydroureter [1].
  • Foxc1 is expressed in both the epithelium of the lacrimal gland and the surrounding mesenchyme [14].
  • The murine Foxc1/Mf1 and Foxc2/Mfh1 genes encode closely related forkhead/winged helix transcription factors with overlapping expression in the forming somites and head mesoderm and endothelial and mesenchymal cells of the developing heart and blood vessels [13].
  • In gain of function studies in the chick embryo, Foxc1 and Foxc2 negatively regulate intermediate mesoderm formation [16].
  • These heterodimers appear to control: (1) the remodeling of the POM through activation of Eya2-related apoptosis; (2) the expression of Foxc1 and Pitx2, which play crucial roles in anterior eye segment development; and (3) the growth of the ventral retina [17].

Associations of Foxc1 with chemical compounds


Other interactions of Foxc1

  • This study demonstrates that Foxc1 mediates the BMP signaling required for lacrimal gland development [14].
  • We also show that BMP-induced expression of Msx2 and Alx4 requires Foxc1 [15].
  • We have shown previously that the winged helix transcription factor Foxc1, which is necessary for calvarial bone development, is required for the Bmp regulation of Msx2 [22].
  • We also localized a second member of this gene family ( Hfh1 ), a candidate for other developmental defects, approximately 470 kb proximal to Mf1 [23].
  • MF-1 RNA is present in non-notochordal mesoderm, and in neural-crest-derived head mesenchyme, while MF-2 transcripts are found in the sclerotomes of the somites and in head mesenchyme, including that from neural crest [24].

Analytical, diagnostic and therapeutic context of Foxc1

  • In order to evaluate its contribution to normal heart septation and valve formation, expression of the mouse homologue Mf1 in embryonic hearts was analyzed by in situ hybridization [3].
  • Electron microscopy combined with a quantitative analysis was used to study the virus-like particles appearing in oocytes and preimplantation embryos of nine mouse strains: inbred AKR, NZB, BALB/c, and C3H/He; randomized Swiss; inbred DDK; noninbred Peru; and randombred Q and MF1 [25].
  • Subcutaneous injection of Rama 900 into thymectomised rats or MF1 nu/nu mice yielded fewer tumours, most of which regressed [26].
  • Northern blot hybridisation reveals that the most abundant MIP mRNA transcript in the adult CAT lens is truncated when compared to that in the adult MF1 lens [27].
  • BALB/c and MF1 mice were examined; as well as transgenic mice with the gene defect of cystic fibrosis (CF) in the airways as an animal model for this disease [28].


  1. Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract. Kume, T., Deng, K., Hogan, B.L. Development (2000) [Pubmed]
  2. The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Seo, S., Fujita, H., Nakano, A., Kang, M., Duarte, A., Kume, T. Dev. Biol. (2006) [Pubmed]
  3. Expression of the Mf1 gene in developing mouse hearts: implication in the development of human congenital heart defects. Swiderski, R.E., Reiter, R.S., Nishimura, D.Y., Alward, W.L., Kalenak, J.W., Searby, C.S., Stone, E.M., Sheffield, V.C., Lin, J.J. Dev. Dyn. (1999) [Pubmed]
  4. Long-term transgene expression by administration of a lentivirus-based vector to the fetal circulation of immuno-competent mice. Waddington, S.N., Mitrophanous, K.A., Ellard, F.M., Buckley, S.M., Nivsarkar, M., Lawrence, L., Cook, H.T., Al-Allaf, F., Bigger, B., Kingsman, S.M., Coutelle, C., Themis, M. Gene Ther. (2003) [Pubmed]
  5. Foetal gene delivery in mice by intra-amniotic administration of retroviral producer cells and adenovirus. Douar, A.M., Adebakin, S., Themis, M., Pavirani, A., Cook, T., Coutelle, C. Gene Ther. (1997) [Pubmed]
  6. Metabolic and behavioural consequences of the procedures of the doubly labelled water technique on white (MF1) mice. Speakman, J.R., Racey, P.A., Burnett, A.M. J. Exp. Biol. (1991) [Pubmed]
  7. Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice. Yalcin, B., Willis-Owen, S.A., Fullerton, J., Meesaq, A., Deacon, R.M., Rawlins, J.N., Copley, R.R., Morris, A.P., Flint, J., Mott, R. Nat. Genet. (2004) [Pubmed]
  8. The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus. Kume, T., Deng, K.Y., Winfrey, V., Gould, D.B., Walter, M.A., Hogan, B.L. Cell (1998) [Pubmed]
  9. Strain-dependent epithelial defects in mice lacking the EGF receptor. Sibilia, M., Wagner, E.F. Science (1995) [Pubmed]
  10. Relevance of Chlamydia pneumoniae murine pneumonitis model to evaluation of antimicrobial agents. Masson, N.D., Toseland, C.D., Beale, A.S. Antimicrob. Agents Chemother. (1995) [Pubmed]
  11. Effects of cisplatin on the mouse testis. Vawda, A.I., Davies, A.G. Acta Endocrinol. (1986) [Pubmed]
  12. Erythrocyte glyoxalase activity in genetically obese (ob/ob) and streptozotocin diabetic mice. Atkins, T.W., Thornally, P.J. Diabetes Res. (1989) [Pubmed]
  13. The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis. Kume, T., Jiang, H., Topczewska, J.M., Hogan, B.L. Genes Dev. (2001) [Pubmed]
  14. The role of the forkhead transcription factor, Foxc1, in the development of the mouse lacrimal gland. Mattiske, D., Sommer, P., Kidson, S.H., Hogan, B.L. Dev. Dyn. (2006) [Pubmed]
  15. Progression of calvarial bone development requires Foxc1 regulation of Msx2 and Alx4. Rice, R., Rice, D.P., Olsen, B.R., Thesleff, I. Dev. Biol. (2003) [Pubmed]
  16. The forkhead genes, Foxc1 and Foxc2, regulate paraxial versus intermediate mesoderm cell fate. Wilm, B., James, R.G., Schultheiss, T.M., Hogan, B.L. Dev. Biol. (2004) [Pubmed]
  17. Retinoic acid-dependent eye morphogenesis is orchestrated by neural crest cells. Matt, N., Dupé, V., Garnier, J.M., Dennefeld, C., Chambon, P., Mark, M., Ghyselinck, N.B. Development (2005) [Pubmed]
  18. Characterization of plasma membrane domains of mouse EL4 lymphoma cells obtained by affinity chromatography on concanavalin A-Sepharose. Szamel, M., Goppelt, M., Resch, K. Biochim. Biophys. Acta (1985) [Pubmed]
  19. An electrophysiological study of parthenogenetic activation in mammalian oocytes. Eusebi, F., Siracusa, G. Dev. Biol. (1983) [Pubmed]
  20. Analysis of the regional uptake of radiolabeled deoxyglucose analogs in human tumor xenografts. Dearling, J.L., Flynn, A.A., Sutcliffe-Goulden, J., Petrie, I.A., Boden, R., Green, A.J., Boxer, G.M., Begent, R.H., Pedley, R.B. J. Nucl. Med. (2004) [Pubmed]
  21. Strain-dependent variation in vascular responses to nitric oxide in the isolated murine heart. Bendall, J.K., Heymes, C., Wright, T.J., Wheatcroft, S., Grieve, D.J., Shah, A.M., Cave, A.C. J. Mol. Cell. Cardiol. (2002) [Pubmed]
  22. Foxc1 integrates Fgf and Bmp signalling independently of twist or noggin during calvarial bone development. Rice, R., Rice, D.P., Thesleff, I. Dev. Dyn. (2005) [Pubmed]
  23. Pleiotropic skeletal and ocular phenotypes of the mouse mutation congenital hydrocephalus (ch/Mf1) arise from a winged helix/forkhead transcriptionfactor gene. Hong, H.K., Lass, J.H., Chakravarti, A. Hum. Mol. Genet. (1999) [Pubmed]
  24. Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo. Sasaki, H., Hogan, B.L. Development (1993) [Pubmed]
  25. Early mouse embryo intracisternal particle: Fourth type of retrovirus-like particle associated with the mouse. Yotsuyanagi, Y., Szöllösi, D. J. Natl. Cancer Inst. (1981) [Pubmed]
  26. Isolation and properties of cell lines from the metastasising rat mammary tumour SMT-2A. Rudland, P.S., Dunnington, D.J., Kim, U., Gusterson, B.A., O'Hare, M.J., Monaghan, P. Br. J. Cancer (1989) [Pubmed]
  27. Aberrant expression of the gene for lens major intrinsic protein in the CAT mouse. Shiels, A., Griffin, C.S. Curr. Eye Res. (1993) [Pubmed]
  28. Immunohistological characterization of leukocytes in the lungs of healthy mice and after bacterial intratracheal infection. Heitmann, S., Tschernig, T., Larbig, M., Steinmetz, I., Hedrich, H.J., Pabst, R. Lab. Anim. (1999) [Pubmed]
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