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Gene Review

Foxc2  -  forkhead box C2

Mus musculus

Synonyms: BF-3, Brain factor 3, Fkh14, Fkhl14, Forkhead box protein C2, ...
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Disease relevance of Foxc2


High impact information on Foxc2

  • In addition, an abnormally large proportion of skin lymphatic vessels was covered with smooth muscle cells in individuals with LD and in mice heterozygous for Foxc2 and for the gene encoding lymphatic endothelial receptor, Vegfr3 (also known as Flt4) [5].
  • 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 [6].
  • In support of this hypothesis, we show here that compound Foxc1; Foxc2 homozygotes die earlier and with much more severe defects than single homozygotes alone [6].
  • Mouse embryos that are compound null mutants for Foxc1 and the closely related Foxc2 have no morphological somites and show abnormal expression of Notch signaling pathway genes in the anterior PSM [7].
  • The winged helix transcription factor MFH1 is required for proliferation and patterning of paraxial mesoderm in the mouse embryo [8].

Biological context of Foxc2

  • Embryos lacking either Foxc1 or Foxc2, and most compound heterozygotes, die pre- or perinatally with similar abnormal phenotypes, including defects in the axial skeleton and cardiovascular system [6].
  • We conclude that Foxc2 haploinsufficient mice mimic closely the distinctive lymphatic and ocular phenotype of LD patients [9].
  • This Foxc2 mutant mouse thus provides an ideal model for exploring molecular mechanisms and physiologic events in mesenchymal differentiation associated with lymphatic growth and development and the clinical abnormalities seen in human LD syndrome [9].
  • We find that TNF alpha and insulin induce Foxc2 mRNA in differentiated 3T3-L1 cells with the kinetics of an immediate early response (1-2 h with 100 ng/ml insulin or 5 ng/ml TNF alpha) [3].
  • This nonallelic noncomplementation and the similar patterns of expression of the two genes in the mesenchyme and endothelial cells of the branchial arches, outflow tract, and heart suggest that Mf1 and Mfh1 play interactive roles in the morphogenesis of the cardiovascular system [10].

Anatomical context of Foxc2

  • For the earliest podocyte marker identified, Foxc2, knockout mice were used to analyze the role of this protein during glomerular development [11].
  • This study was performed to elucidate the hormonal regulation of Foxc2 in adipocytes [3].
  • The forkhead genes, Foxc1 and Foxc2, regulate paraxial versus intermediate mesoderm cell fate [12].
  • In gain of function studies in the chick embryo, Foxc1 and Foxc2 negatively regulate intermediate mesoderm formation [12].
  • Previous studies have shown that Mfh1 null mutants have severe cardiovascular defects, including interruptions and coarctations of the aortic arch and ventricular septal defects (Iida et al., Development 124, 4627-4638, 1997) [10].

Associations of Foxc2 with chemical compounds


Regulatory relationships of Foxc2

  • Also, signaling pathways downstream of PKA and PKC induce the expression of Foxc2 mRNA [3].
  • Treatment with BMP-4/7 and BMP-7 protein also enhanced Mfh1 expression in C1 cells [13].

Other interactions of Foxc2

  • The morphological defects in Mfh1/Pax1 double mutants strongly correlate with the reduction of the mitotic rate of sclerotome cells [4].
  • Among them, we found that the expression of MFH-1 (mesenchyme forkhead-1), which was reported to regulate the proliferation and differentiation of sclerotome cells, was significantly reduced in ventromedial sclerotome cells in Bapx1-/- mice [15].
  • The other two are novel and have been named MF-1 and MF-2 (for mesoderm/mesenchyme fork head) [16].
  • In 12.5 dpc and 13.5 dpc embryos, the expression of Mfh1 was localized to the perichondrium, which surrounds cells that express noggin and SOX9 mRNA [13].
  • Thus, both the Mfh1 and the Pax1 gene products cooperate to mediate Sonic hedgehog-dependent proliferation of sclerotome cells [4].

Analytical, diagnostic and therapeutic context of Foxc2

  • We first examined expression patterns of Mfh1 in relation to the cartilage phenotype-related molecules including bone morphogenetic proteins (BMPs) during mouse embryogenesis by in situ hybridization [13].
  • To further examine the causative relationship between BMP and Mfh1 in mesenchymal tissue, we performed a mouse limb bud organ culture to implant BMP proteins with carriers into the mesenchymal tissue of the limb bud [13].


  1. 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]
  2. Roles of forkhead transcription factor Foxc2 (MFH-1) and endothelin receptor A in cardiovascular morphogenesis. Kanzaki-Kato, N., Tamakoshi, T., Fu, Y., Chandra, A., Itakura, T., Uezato, T., Tanaka, T., Clouthier, D.E., Sugiyama, T., Yanagisawa, M., Miura, N. Cardiovasc. Res. (2005) [Pubmed]
  3. Insulin and TNF alpha induce expression of the forkhead transcription factor gene Foxc2 in 3T3-L1 adipocytes via PI3K and ERK 1/2-dependent pathways. Grønning, L.M., Cederberg, A., Miura, N., Enerbäck, S., Taskén, K. Mol. Endocrinol. (2002) [Pubmed]
  4. Notochord-dependent expression of MFH1 and PAX1 cooperates to maintain the proliferation of sclerotome cells during the vertebral column development. Furumoto, T.A., Miura, N., Akasaka, T., Mizutani-Koseki, Y., Sudo, H., Fukuda, K., Maekawa, M., Yuasa, S., Fu, Y., Moriya, H., Taniguchi, M., Imai, K., Dahl, E., Balling, R., Pavlova, M., Gossler, A., Koseki, H. Dev. Biol. (1999) [Pubmed]
  5. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Petrova, T.V., Karpanen, T., Norrmén, C., Mellor, R., Tamakoshi, T., Finegold, D., Ferrell, R., Kerjaschki, D., Mortimer, P., Ylä-Herttuala, S., Miura, N., Alitalo, K. Nat. Med. (2004) [Pubmed]
  6. 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]
  7. The winged helix transcription factor Foxc1a is essential for somitogenesis in zebrafish. Topczewska, J.M., Topczewski, J., Shostak, A., Kume, T., Solnica-Krezel, L., Hogan, B.L. Genes Dev. (2001) [Pubmed]
  8. The winged helix transcription factor MFH1 is required for proliferation and patterning of paraxial mesoderm in the mouse embryo. Winnier, G.E., Hargett, L., Hogan, B.L. Genes Dev. (1997) [Pubmed]
  9. FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome. Kriederman, B.M., Myloyde, T.L., Witte, M.H., Dagenais, S.L., Witte, C.L., Rennels, M., Bernas, M.J., Lynch, M.T., Erickson, R.P., Caulder, M.S., Miura, N., Jackson, D., Brooks, B.P., Glover, T.W. Hum. Mol. Genet. (2003) [Pubmed]
  10. Roles for the winged helix transcription factors MF1 and MFH1 in cardiovascular development revealed by nonallelic noncomplementation of null alleles. Winnier, G.E., Kume, T., Deng, K., Rogers, R., Bundy, J., Raines, C., Walter, M.A., Hogan, B.L., Conway, S.J. Dev. Biol. (1999) [Pubmed]
  11. Large-scale identification of genes implicated in kidney glomerulus development and function. Takemoto, M., He, L., Norlin, J., Patrakka, J., Xiao, Z., Petrova, T., Bondjers, C., Asp, J., Wallgard, E., Sun, Y., Samuelsson, T., Mostad, P., Lundin, S., Miura, N., Sado, Y., Alitalo, K., Quaggin, S.E., Tryggvason, K., Betsholtz, C. EMBO J. (2006) [Pubmed]
  12. 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]
  13. Bone morphogenetic protein regulation of forkhead/winged helix transcription factor Foxc2 (Mfh1) in a murine mesodermal cell line C1 and in skeletal precursor cells. Nifuji, A., Miura, N., Kato, N., Kellermann, O., Noda, M. J. Bone Miner. Res. (2001) [Pubmed]
  14. LMX1B, a LIM homeodomain class transcription factor, is necessary for normal development of multiple tissues in the anterior segment of the murine eye. Pressman, C.L., Chen, H., Johnson, R.L. Genesis (2000) [Pubmed]
  15. Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation. Akazawa, H., Komuro, I., Sugitani, Y., Yazaki, Y., Nagai, R., Noda, T. Genes Cells (2000) [Pubmed]
  16. 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]
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