FOXC1_MOUSE
ID FOXC1_MOUSE Reviewed; 553 AA.
AC Q61572; O88409; Q61582; Q9QWR9;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Forkhead box protein C1;
DE AltName: Full=Forkhead-related protein FKHL7;
DE AltName: Full=Forkhead-related transcription factor 3;
DE Short=FREAC-3;
DE AltName: Full=Mesoderm/mesenchyme forkhead 1;
DE Short=MF-1;
DE AltName: Full=Transcription factor FKH-1;
GN Name=Foxc1; Synonyms=Fkh1, Fkhl7, Freac3, Mf1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=9635428; DOI=10.1016/s0092-8674(00)81204-0;
RA Kume T., Deng K.Y., Winfrey V., Gould D.B., Walter M.A., Hogan B.L.M.;
RT "The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse
RT mutation congenital hydrocephalus.";
RL Cell 93:985-996(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Embryo;
RX PubMed=9767123; DOI=10.1016/s0378-1119(98)00409-0;
RA Hiemisch H., Schutz G., Kaestner K.H.;
RT "The mouse Fkh1/Mf1 gene: cDNA sequence, chromosomal localization and
RT expression in adult tissues.";
RL Gene 220:77-82(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Diencephalon;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Embryonic brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 69-179.
RC STRAIN=129;
RX PubMed=7689224; DOI=10.1073/pnas.90.16.7628;
RA Kaestner K.H., Lee K.H., Schloendorff J., Hiemisch H., Monaghan A.P.,
RA Schuetz G.;
RT "Six members of the mouse forkhead gene family are developmentally
RT regulated.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:7628-7631(1993).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 71-187.
RX PubMed=8375339; DOI=10.1242/dev.118.1.47;
RA Sasaki H., Hogan B.L.;
RT "Differential expression of multiple fork head related genes during
RT gastrulation and axial pattern formation in the mouse embryo.";
RL Development 118:47-59(1993).
RN [7]
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=9106663; DOI=10.1101/gad.11.7.926;
RA Winnier G.E., Hargett L., Hogan B.L.;
RT "The winged helix transcription factor MFH1 is required for proliferation
RT and patterning of paraxial mesoderm in the mouse embryo.";
RL Genes Dev. 11:926-940(1997).
RN [8]
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=10395790; DOI=10.1006/dbio.1999.9314;
RA Kidson S.H., Kume T., Deng K., Winfrey V., Hogan B.L.;
RT "The forkhead/winged-helix gene, Mf1, is necessary for the normal
RT development of the cornea and formation of the anterior chamber in the
RT mouse eye.";
RL Dev. Biol. 211:306-322(1999).
RN [9]
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=10479458; DOI=10.1006/dbio.1999.9382;
RA Winnier G.E., Kume T., Deng K., Rogers R., Bundy J., Raines C.,
RA Walter M.A., Hogan B.L., Conway S.J.;
RT "Roles for the winged helix transcription factors MF1 and MFH1 in
RT cardiovascular development revealed by nonallelic noncomplementation of
RT null alleles.";
RL Dev. Biol. 213:418-431(1999).
RN [10]
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=10704385; DOI=10.1242/dev.127.7.1387;
RA Kume T., Deng K., Hogan B.L.;
RT "Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are
RT required for the early organogenesis of the kidney and urinary tract.";
RL Development 127:1387-1395(2000).
RN [11]
RP FUNCTION, DISRUPTION PHENOTYPE, DEVELOPMENTAL STAGE, AND SUBCELLULAR
RP LOCATION.
RX PubMed=11562355; DOI=10.1101/gad.907301;
RA Kume T., Jiang H., Topczewska J.M., Hogan B.L.;
RT "The murine winged helix transcription factors, Foxc1 and Foxc2, are both
RT required for cardiovascular development and somitogenesis.";
RL Genes Dev. 15:2470-2482(2001).
RN [12]
RP FUNCTION, DISRUPTION PHENOTYPE, AND CONDITIONAL KNOCKOUT.
RX PubMed=15196959; DOI=10.1016/j.ydbio.2004.03.034;
RA Wilm B., James R.G., Schultheiss T.M., Hogan B.L.;
RT "The forkhead genes, Foxc1 and Foxc2, regulate paraxial versus intermediate
RT mesoderm cell fate.";
RL Dev. Biol. 271:176-189(2004).
RN [13]
RP DEVELOPMENTAL STAGE.
RX PubMed=16449236; DOI=10.1093/hmg/ddl008;
RA Berry F.B., Lines M.A., Oas J.M., Footz T., Underhill D.A., Gage P.J.,
RA Walter M.A.;
RT "Functional interactions between FOXC1 and PITX2 underlie the sensitivity
RT to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment
RT dysgenesis.";
RL Hum. Mol. Genet. 15:905-919(2006).
RN [14]
RP FUNCTION, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE, AND CONDITIONAL
RP KNOCKOUT.
RX PubMed=18187037; DOI=10.1016/j.bbrc.2007.12.183;
RA Hayashi H., Kume T.;
RT "Forkhead transcription factors regulate expression of the chemokine
RT receptor CXCR4 in endothelial cells and CXCL12-induced cell migration.";
RL Biochem. Biophys. Res. Commun. 367:584-589(2008).
RN [15]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=19668217; DOI=10.1038/ng.422;
RA Aldinger K.A., Lehmann O.J., Hudgins L., Chizhikov V.V., Bassuk A.G.,
RA Ades L.C., Krantz I.D., Dobyns W.B., Millen K.J.;
RT "FOXC1 is required for normal cerebellar development and is a major
RT contributor to chromosome 6p25.3 Dandy-Walker malformation.";
RL Nat. Genet. 41:1037-1042(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-237 AND SER-243, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [17]
RP FUNCTION, SUMOYLATION, PHOSPHORYLATION AT SER-237; SER-243; SER-320 AND
RP SER-521, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 6-SER--SER-9; LYS-229;
RP SER-237; SER-243; LYS-258; SER-320 AND SER-521.
RX PubMed=22493429; DOI=10.1074/jbc.m112.339424;
RA Danciu T.E., Chupreta S., Cruz O., Fox J.E., Whitman M.,
RA Iniguez-Lluhi J.A.;
RT "Small ubiquitin-like modifier (SUMO) modification mediates function of the
RT inhibitory domains of developmental regulators FOXC1 and FOXC2.";
RL J. Biol. Chem. 287:18318-18329(2012).
RN [18]
RP FUNCTION, DISRUPTION PHENOTYPE, AND CONDITIONAL KNOCKOUT.
RX PubMed=22171010; DOI=10.1073/pnas.1109540109;
RA Seo S., Singh H.P., Lacal P.M., Sasman A., Fatima A., Liu T., Schultz K.M.,
RA Losordo D.W., Lehmann O.J., Kume T.;
RT "Forkhead box transcription factor FoxC1 preserves corneal transparency by
RT regulating vascular growth.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:2015-2020(2012).
RN [19]
RP FUNCTION, DISRUPTION PHENOTYPE, CONDITIONAL KNOCKOUT, TISSUE SPECIFICITY,
RP AND DEVELOPMENTAL STAGE.
RX PubMed=24590069; DOI=10.1038/nature13071;
RA Omatsu Y., Seike M., Sugiyama T., Kume T., Nagasawa T.;
RT "Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche
RT formation.";
RL Nature 508:536-540(2014).
RN [20]
RP INTERACTION WITH GLI2.
RX PubMed=26565916; DOI=10.1016/j.celrep.2015.09.063;
RA Han B., Qu Y., Jin Y., Yu Y., Deng N., Wawrowsky K., Zhang X., Li N.,
RA Bose S., Wang Q., Sakkiah S., Abrol R., Jensen T.W., Berman B.P.,
RA Tanaka H., Johnson J., Gao B., Hao J., Liu Z., Buttyan R., Ray P.S.,
RA Hung M.C., Giuliano A.E., Cui X.;
RT "FOXC1 activates smoothened-independent Hedgehog signaling in basal-like
RT breast cancer.";
RL Cell Rep. 13:1046-1058(2015).
RN [21]
RP FUNCTION, INTERACTION WITH GLI2, SUBCELLULAR LOCATION, DISRUPTION
RP PHENOTYPE, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND MUTAGENESIS OF
RP PHE-112.
RX PubMed=25808752; DOI=10.1038/ncomms7653;
RA Yoshida M., Hata K., Takashima R., Ono K., Nakamura E., Takahata Y.,
RA Murakami T., Iseki S., Takano-Yamamoto T., Nishimura R., Yoneda T.;
RT "The transcription factor Foxc1 is necessary for Ihh-Gli2-regulated
RT endochondral ossification.";
RL Nat. Commun. 6:6653-6653(2015).
RN [22]
RP FUNCTION, DISRUPTION PHENOTYPE, CONDITIONAL KNOCKOUTS, AND TISSUE
RP SPECIFICITY.
RX PubMed=28223138; DOI=10.1016/j.yexcr.2017.02.016;
RA Motojima M., Kume T., Matsusaka T.;
RT "Foxc1 and Foxc2 are necessary to maintain glomerular podocytes.";
RL Exp. Cell Res. 352:265-272(2017).
CC -!- FUNCTION: DNA-binding transcriptional factor that plays a role in a
CC broad range of cellular and developmental processes such as eye, bones,
CC cardiovascular, kidney and skin development (PubMed:9635428,
CC PubMed:9106663, PubMed:10479458, PubMed:10395790, PubMed:11562355,
CC PubMed:18187037, PubMed:19668217, PubMed:22493429, PubMed:24590069,
CC PubMed:25808752, PubMed:28223138). Acts either as a transcriptional
CC activator or repressor (PubMed:28223138). Binds to the consensus
CC binding site 5'-[G/C][A/T]AAA[T/C]AA[A/C]-3' in promoter of target
CC genes (PubMed:25808752). Upon DNA-binding, promotes DNA bending. Acts
CC as a transcriptional coactivator (PubMed:25808752). Stimulates Indian
CC hedgehog (Ihh)-induced target gene expression mediated by the
CC transcription factor GLI2, and hence regulates endochondral
CC ossification (PubMed:25808752). Acts also as a transcriptional
CC coregulator by increasing DNA-binding capacity of GLI2 in breast cancer
CC cells. Regulates FOXO1 through binding to a conserved element, 5'-
CC GTAAACAAA-3' in its promoter region, implicating FOXC1 as an important
CC regulator of cell viability and resistance to oxidative stress in the
CC eye (By similarity). Cooperates with transcription factor FOXC2 in
CC regulating expression of genes that maintain podocyte integrity
CC (PubMed:28223138). Promotes cell growth inhibition by stopping the cell
CC cycle in the G1 phase through TGFB1-mediated signals. Involved in
CC epithelial-mesenchymal transition (EMT) induction by increasing cell
CC proliferation, migration and invasion (By similarity). Involved in
CC chemokine CXCL12-induced endothelial cell migration through the control
CC of CXCR4 expression (PubMed:18187037). Plays a role in the gene
CC regulatory network essential for epidermal keratinocyte terminal
CC differentiation (By similarity). Essential developmental
CC transcriptional factor required for mesoderm-derived tissues formation,
CC such as the somites, skin, bone and cartilage (PubMed:9106663,
CC PubMed:10479458, PubMed:10395790, PubMed:10704385, PubMed:11562355,
CC PubMed:15196959). Positively regulates CXCL12 and stem cell factor
CC expression in bone marrow mesenchymal progenitor cells, and hence plays
CC a role in the development and maintenance of mesenchymal niches for
CC haematopoietic stem and progenitor cells (HSPC) (PubMed:24590069).
CC Plays a role in corneal transparency by preventing both blood vessel
CC and lymphatic vessel growth during embryonic development in a VEGF-
CC dependent manner (PubMed:22171010). May function as a tumor suppressor
CC (By similarity). {ECO:0000250|UniProtKB:Q12948,
CC ECO:0000269|PubMed:10395790, ECO:0000269|PubMed:10479458,
CC ECO:0000269|PubMed:10704385, ECO:0000269|PubMed:11562355,
CC ECO:0000269|PubMed:15196959, ECO:0000269|PubMed:18187037,
CC ECO:0000269|PubMed:19668217, ECO:0000269|PubMed:22171010,
CC ECO:0000269|PubMed:22493429, ECO:0000269|PubMed:24590069,
CC ECO:0000269|PubMed:25808752, ECO:0000269|PubMed:28223138,
CC ECO:0000269|PubMed:9106663, ECO:0000269|PubMed:9635428}.
CC -!- SUBUNIT: Monomer. Interacts with C1QBP (By similarity). Interacts (via
CC N-terminus) with GLI2 (via C-terminal internal region); this
CC interaction is direct and increases GLI2 DNA-binding and
CC transcriptional activity through a smoothened (SMO)-independent
CC Hedgehog (Hh) signaling pathway (PubMed:26565916, PubMed:25808752).
CC Interacts (via C-terminus domain) with PITX2 (via homeobox domain) (By
CC similarity). Interacts with FLNA and PBX1 (By similarity).
CC {ECO:0000250|UniProtKB:Q12948, ECO:0000269|PubMed:25808752,
CC ECO:0000269|PubMed:26565916}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11562355,
CC ECO:0000269|PubMed:22493429, ECO:0000269|PubMed:25808752}.
CC Note=Colocalizes with PITX2 in the nucleus at subnuclear chromatin
CC regions. Colocalizes with CBX5 to a heterochromatin-rich region of the
CC nucleus (By similarity). Colocalizes with GLI2 in the nucleus
CC (PubMed:25808752). {ECO:0000250|UniProtKB:Q12948,
CC ECO:0000269|PubMed:25808752}.
CC -!- TISSUE SPECIFICITY: Expressed in glomerular epithelial cells, the
CC podocytes (PubMed:28223138). Expressed in a population of adipo-
CC osteogenic progenitor cells, termed CXCL12-abundant reticular (CAR)
CC cells (at protein level) (PubMed:24590069). Expressed in many embryonic
CC tissues, including prechondrogenic mesenchyme, periocular mesenchyme,
CC meninges, endothelial cells and kidney (PubMed:9767123). Detected in
CC adult brain, heart, kidney, adrenal gland, lung and testis, with lower
CC levels in stomach, spleen and thymus (PubMed:9767123). Expressed in
CC endothelial cells (PubMed:18187037). Expressed in the mesenchyme
CC adjacent to the developing cerebellum (PubMed:19668217). Expressed in
CC the sternum and rib cartilage (PubMed:25808752). Expressed in growth
CC plate chondrocytes (PubMed:25808752). {ECO:0000269|PubMed:18187037,
CC ECO:0000269|PubMed:19668217, ECO:0000269|PubMed:24590069,
CC ECO:0000269|PubMed:25808752, ECO:0000269|PubMed:28223138,
CC ECO:0000269|PubMed:9767123}.
CC -!- DEVELOPMENTAL STAGE: Expressed in the anterior presomitic mesoderm
CC (PSM) and somites at 9.5 dpc. Expressed in endothelial and smooth
CC muscle cells of blood vessels at 9.5 dpc (PubMed:11562355). Expressed
CC in growth plate chondrocytes and perichondrial cells at 13.5 dpc (at
CC protein level) (PubMed:25808752). Expressed in non-notochordal mesoderm
CC surrounding the node and notochord at 7.5 dpc (PubMed:9106663).
CC Expressed in anterior presomitic mesoderm adjacent to somites, in the
CC somites, and in the cephalic mesoderm at 8.5 and 9.5 dpc
CC (PubMed:9106663). Detected weakly in yolk sac at 9.5 dpc
CC (PubMed:11562355). Expressed in presumptive intermediate mesoderm, as
CC well as in the presomitic mesoderm and somites at 8.5 and 9.5 dpc
CC (PubMed:10704385). Expressed in the metanephric mesenchyme of the
CC kidney at 10.5 and 12.5 dpc (PubMed:10704385). Expressed during the
CC developing cardiovascular system (PubMed:10479458). Expressed in the
CC branchial arches and mesenchymal cells surrounding the eye at 10.5 dpc
CC (PubMed:9106663). Expressed in nasal processes, corneal mesenchyme
CC cells, branchial arches, blood vessels and endocardium at 11.5 dpc
CC (PubMed:9106663, PubMed:10395790). Expressed in cells located in the
CC presumptive anterior segment that are fated to contribute to the
CC corneal endothelium or stroma, as well as within cells located at the
CC periphery of the optic cup at 11.5 dpc (PubMed:16449236). Expressed in
CC periocular mesenchyme cells at 11.5, 12.5 and 16.5 dpc
CC (PubMed:10395790, PubMed:16449236). Expressed in developing limb buds
CC at 12.5 dpc (PubMed:25808752). Expressed in chondrocytes at 15 dpc
CC (PubMed:25808752). Expressed in the trabecular meshwork cells, the
CC sclera, the conjunctival epithelium and the corneal epithelium at 16.5
CC dpc (PubMed:10395790). Strongly expressed in adipo-osteogenic
CC progenitor cells (CXCL12-abundant reticular (CAR) cells) at 16.5 dpc
CC and at birth (PubMed:24590069). {ECO:0000269|PubMed:10395790,
CC ECO:0000269|PubMed:10479458, ECO:0000269|PubMed:10704385,
CC ECO:0000269|PubMed:11562355, ECO:0000269|PubMed:16449236,
CC ECO:0000269|PubMed:24590069, ECO:0000269|PubMed:25808752,
CC ECO:0000269|PubMed:9106663}.
CC -!- PTM: Phosphorylated (PubMed:22493429). Phosphorylated on Ser-274 in
CC response to epidermal growth factor (EGF) in a ERK1/2 MAPK-dependent
CC signaling pathway; phosphorylation contributes to its protein stability
CC and transcriptional regulatory activity (By similarity).
CC {ECO:0000250|UniProtKB:Q12948, ECO:0000269|PubMed:22493429}.
CC -!- PTM: Sumoylated preferentially with SUMO2 or SUMO3. Desumoylated by
CC SENP2. {ECO:0000269|PubMed:22493429}.
CC -!- PTM: Ubiquitinated, leading to its proteasomal degradation.
CC {ECO:0000250|UniProtKB:Q12948}.
CC -!- DISRUPTION PHENOTYPE: Embryos die pre- and perinatally with
CC haemorrhagic hydrocephalus and calvarial defects, beginning at 13.5 dpc
CC (PubMed:9635428, PubMed:10479458, PubMed:19668217). Mutants that
CC survive to later stages exhibit multiple craniofacial and vertebral
CC defects characterized by disorganized rib fusion, absence of
CC chondrocytes proliferation and ossification (PubMed:9106663,
CC PubMed:25808752). Show abnormal cerebellar development with an enlarged
CC fourth ventricle roof plate at 12.5 dpc and a disorganized cerebellar
CC rhombic lip (PubMed:19668217). Show eye formation abnormalities: the
CC lens remains attached to the cornea, both the anterior chamber and the
CC corneal endothelium are absent, the corneal stroma is thicker, the
CC arrangement of mesenchyme cells are disorganized and the corneal
CC endothelial cells do not differentiate (PubMed:10395790). Show
CC cardiovascular defects including persistent truncus arteriosus,
CC ventricular septal defect, coarctation of the aortic arch, and aortic
CC and pulmonary valve dysplasia (PubMed:10479458). Show abnormal kidney
CC and ureter development, including duplex kidneys connecting to double
CC ureters (PubMed:10704385). Show a decrease in hedgehog-induced genes
CC expression levels involved in endochondral ossification
CC (PubMed:25808752). Double knockout of FOXC1 and FOXC2 genes in mice
CC embryos die around 8-9.5 dpc and show profound abnormalities in the
CC first and second branchial arches, the early remodeling of blood
CC vessels, a complete absence of segmented paraxial mesoderm, and the
CC presence of ectopic and disorganized mesonephric kidney tubules
CC (PubMed:11562355, PubMed:15196959). Mice with conditional knockout of
CC both FOXC1 and FOXC2 genes in adult mice show renal tubular damage with
CC protein reabsorption droplets, tubular dilation and proteinaceous casts
CC and show also altered expression levels for several genes involved in
CC the differentiation of podocytes (PubMed:28223138). Display also
CC podocyte degeneration characterized with microvillous transformation,
CC podocyte foot process effacement and irregular thickness of the
CC glomerular basement membrane (PubMed:28223138). Podocyte-cell-specific
CC conditional knockout of both FOXC1 and FOXC2 genes in adult mice show
CC reabsorption droplets, tubular dilation and proteinaceous casts
CC (PubMed:28223138). Endothelial-specific conditional knockout mice show
CC a significant reduction in CXCR4 expression as well as in chemokine
CC CXCL12-induced endothelial cell migration (PubMed:18187037). Limb bud
CC mesenchymal-specific conditional knockout mice display strong reduction
CC in haematopoietic stem and progenitor cells, the presence of adipocytes
CC in marrow cavities (yellow adipose marrow) instead of CXCL12-abundant
CC reticular (CAR) cells and die around 6 weeks of age with haemorrhagic
CC hydrocephalus and calvarial defects (PubMed:24590069). CAR cell-
CC specific conditional knockout mice are viable and die without
CC hydrocephalus defects, but show a reduction in haematopoietic stem and
CC progenitor cells (HSPCs) and most marrow cavities are filled with
CC adipocytes (PubMed:24590069). Adult widespread cell-specific
CC conditional knockout mice show a reduction in haematopoietic stem and
CC progenitor cells (HSPCs), with only occasional adipocytes present in
CC marrow cavities (PubMed:24590069). Neural crest (NC)-specific
CC conditional knockout mice die postnatally with hydrocephalus and
CC craniofacial abnormalities comparable to those seen in conventional
CC knockout mice; embryos display pupillary abnormalities, with impaired
CC collagen formation in the corneal stroma and aberrant vessel growth in
CC the normally avascular corneas (PubMed:22171010).
CC {ECO:0000269|PubMed:10395790, ECO:0000269|PubMed:10479458,
CC ECO:0000269|PubMed:10704385, ECO:0000269|PubMed:11562355,
CC ECO:0000269|PubMed:15196959, ECO:0000269|PubMed:18187037,
CC ECO:0000269|PubMed:19668217, ECO:0000269|PubMed:22171010,
CC ECO:0000269|PubMed:24590069, ECO:0000269|PubMed:25808752,
CC ECO:0000269|PubMed:28223138, ECO:0000269|PubMed:9106663,
CC ECO:0000269|PubMed:9635428}.
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DR EMBL; AF045017; AAC24209.1; -; mRNA.
DR EMBL; AJ223298; CAA11239.1; -; Genomic_DNA.
DR EMBL; AK144420; BAE25882.1; -; mRNA.
DR EMBL; BC052011; AAH52011.1; -; mRNA.
DR EMBL; X71939; CAA50741.1; -; Genomic_DNA.
DR EMBL; L10406; AAA03159.1; -; mRNA.
DR CCDS; CCDS26425.1; -.
DR PIR; I49674; I49674.
DR RefSeq; NP_032618.2; NM_008592.2.
DR AlphaFoldDB; Q61572; -.
DR SMR; Q61572; -.
DR IntAct; Q61572; 3.
DR MINT; Q61572; -.
DR STRING; 10090.ENSMUSP00000052196; -.
DR iPTMnet; Q61572; -.
DR PhosphoSitePlus; Q61572; -.
DR MaxQB; Q61572; -.
DR PaxDb; Q61572; -.
DR PRIDE; Q61572; -.
DR ProteomicsDB; 267511; -.
DR Antibodypedia; 9213; 436 antibodies from 41 providers.
DR DNASU; 17300; -.
DR Ensembl; ENSMUST00000062292; ENSMUSP00000052196; ENSMUSG00000050295.
DR GeneID; 17300; -.
DR KEGG; mmu:17300; -.
DR UCSC; uc007pzp.1; mouse.
DR CTD; 2296; -.
DR MGI; MGI:1347466; Foxc1.
DR VEuPathDB; HostDB:ENSMUSG00000050295; -.
DR eggNOG; KOG2294; Eukaryota.
DR GeneTree; ENSGT00940000162303; -.
DR HOGENOM; CLU_035722_3_0_1; -.
DR InParanoid; Q61572; -.
DR OMA; HCNLQAM; -.
DR OrthoDB; 1270467at2759; -.
DR PhylomeDB; Q61572; -.
DR TreeFam; TF316127; -.
DR BioGRID-ORCS; 17300; 3 hits in 72 CRISPR screens.
DR ChiTaRS; Foxc1; mouse.
DR PRO; PR:Q61572; -.
DR Proteomes; UP000000589; Chromosome 13.
DR RNAct; Q61572; protein.
DR Bgee; ENSMUSG00000050295; Expressed in parotid gland and 277 other tissues.
DR Genevisible; Q61572; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0000792; C:heterochromatin; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0008301; F:DNA binding, bending; ISS:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:GO_Central.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:BHF-UCL.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:MGI.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; ISS:UniProtKB.
DR GO; GO:1990841; F:promoter-specific chromatin binding; IDA:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:GO_Central.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; ISO:MGI.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:MGI.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:BHF-UCL.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0003275; P:apoptotic process involved in outflow tract morphogenesis; IGI:MGI.
DR GO; GO:0048844; P:artery morphogenesis; IMP:MGI.
DR GO; GO:0001568; P:blood vessel development; IGI:MGI.
DR GO; GO:0097746; P:blood vessel diameter maintenance; IGI:MGI.
DR GO; GO:0001974; P:blood vessel remodeling; IGI:MGI.
DR GO; GO:0007420; P:brain development; IMP:MGI.
DR GO; GO:0043010; P:camera-type eye development; IMP:MGI.
DR GO; GO:0060038; P:cardiac muscle cell proliferation; IGI:MGI.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0016477; P:cell migration; ISS:UniProtKB.
DR GO; GO:0008283; P:cell population proliferation; ISS:UniProtKB.
DR GO; GO:1990869; P:cellular response to chemokine; IMP:UniProtKB.
DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; ISS:UniProtKB.
DR GO; GO:0021549; P:cerebellum development; IMP:UniProtKB.
DR GO; GO:0070098; P:chemokine-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0030199; P:collagen fibril organization; IMP:MGI.
DR GO; GO:0035050; P:embryonic heart tube development; IGI:MGI.
DR GO; GO:0001958; P:endochondral ossification; IMP:UniProtKB.
DR GO; GO:0001654; P:eye development; IMP:MGI.
DR GO; GO:0008354; P:germ cell migration; IMP:MGI.
DR GO; GO:0072010; P:glomerular epithelium development; IMP:UniProtKB.
DR GO; GO:0030203; P:glycosaminoglycan metabolic process; IMP:MGI.
DR GO; GO:0007507; P:heart development; IMP:MGI.
DR GO; GO:0003007; P:heart morphogenesis; IGI:MGI.
DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI.
DR GO; GO:0001822; P:kidney development; IMP:MGI.
DR GO; GO:0032808; P:lacrimal gland development; IMP:MGI.
DR GO; GO:0001945; P:lymph vessel development; IGI:MGI.
DR GO; GO:0036438; P:maintenance of lens transparency; IMP:UniProtKB.
DR GO; GO:0014031; P:mesenchymal cell development; IDA:UniProtKB.
DR GO; GO:0048762; P:mesenchymal cell differentiation; IMP:MGI.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IMP:UniProtKB.
DR GO; GO:1902257; P:negative regulation of apoptotic process involved in outflow tract morphogenesis; IGI:MGI.
DR GO; GO:1901491; P:negative regulation of lymphangiogenesis; IMP:UniProtKB.
DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:UniProtKB.
DR GO; GO:0014032; P:neural crest cell development; IGI:MGI.
DR GO; GO:0007219; P:Notch signaling pathway; IGI:MGI.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; ISS:UniProtKB.
DR GO; GO:0001503; P:ossification; IMP:MGI.
DR GO; GO:0001541; P:ovarian follicle development; IMP:MGI.
DR GO; GO:0048341; P:paraxial mesoderm formation; IMP:UniProtKB.
DR GO; GO:1904798; P:positive regulation of core promoter binding; IMP:UniProtKB.
DR GO; GO:0043388; P:positive regulation of DNA binding; ISS:UniProtKB.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISS:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; IDA:UniProtKB.
DR GO; GO:1901534; P:positive regulation of hematopoietic progenitor cell differentiation; IMP:UniProtKB.
DR GO; GO:1902038; P:positive regulation of hematopoietic stem cell differentiation; IMP:UniProtKB.
DR GO; GO:0045618; P:positive regulation of keratinocyte differentiation; ISO:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0046620; P:regulation of organ growth; IGI:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0001501; P:skeletal system development; IMP:MGI.
DR GO; GO:0001756; P:somitogenesis; IGI:UniProtKB.
DR GO; GO:0001657; P:ureteric bud development; IMP:MGI.
DR GO; GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; IGI:MGI.
DR GO; GO:0038084; P:vascular endothelial growth factor signaling pathway; IMP:UniProtKB.
DR GO; GO:0055010; P:ventricular cardiac muscle tissue morphogenesis; IGI:MGI.
DR CDD; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR InterPro; IPR001766; Fork_head_dom.
DR InterPro; IPR033067; FoxC1.
DR InterPro; IPR018122; TF_fork_head_CS_1.
DR InterPro; IPR030456; TF_fork_head_CS_2.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR InterPro; IPR036390; WH_DNA-bd_sf.
DR PANTHER; PTHR11829:SF68; PTHR11829:SF68; 1.
DR Pfam; PF00250; Forkhead; 1.
DR PRINTS; PR00053; FORKHEAD.
DR SMART; SM00339; FH; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR PROSITE; PS00657; FORK_HEAD_1; 1.
DR PROSITE; PS00658; FORK_HEAD_2; 1.
DR PROSITE; PS50039; FORK_HEAD_3; 1.
PE 1: Evidence at protein level;
KW Activator; Angiogenesis; Developmental protein; DNA-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..553
FT /note="Forkhead box protein C1"
FT /id="PRO_0000091807"
FT DNA_BIND 77..168
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 1..51
FT /note="Required for transcriptional activation"
FT /evidence="ECO:0000250|UniProtKB:Q12948"
FT REGION 173..326
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 217..366
FT /note="Required for transcriptional inhibition"
FT /evidence="ECO:0000250|UniProtKB:Q12948"
FT REGION 356..393
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 420..466
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 466..553
FT /note="Required for transcriptional activation"
FT /evidence="ECO:0000250|UniProtKB:Q12948"
FT MOTIF 78..93
FT /note="Nuclear localization signal 1 (NLS 1)"
FT /evidence="ECO:0000250|UniProtKB:Q12948"
FT MOTIF 168..176
FT /note="Nuclear localization signal 2 (NLS 2)"
FT /evidence="ECO:0000250|UniProtKB:Q12948"
FT COMPBIAS 196..223
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 257..280
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 289..303
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 308..323
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 356..375
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 439..455
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 237
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:22493429,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 243
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:22493429,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 274
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12948"
FT MOD_RES 320
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:22493429"
FT MOD_RES 521
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:22493429"
FT MUTAGEN 6..9
FT /note="SVSS->AVAA: No effect on sumoylation; when
FT associated with A-237; A-243; A-320 and A-521."
FT /evidence="ECO:0000269|PubMed:22493429"
FT MUTAGEN 112
FT /note="F->S: Inhibits interaction with GLI2. Decreased
FT nuclear colocalization with GLI2. No effect on DNA-binding.
FT Decreased Ihh-induced transcriptional activity and
FT transcription coactivator activity with GLI2."
FT /evidence="ECO:0000269|PubMed:25808752"
FT MUTAGEN 229
FT /note="K->R: No effect on protein stability, inhibited
FT sumoylation, increased transcriptional activity; when
FT associated with R-258."
FT /evidence="ECO:0000269|PubMed:22493429"
FT MUTAGEN 237
FT /note="S->A: No effect on sumoylation; when associated with
FT 6-A--A-9; A-243; A-320 and A-521."
FT /evidence="ECO:0000269|PubMed:22493429"
FT MUTAGEN 243
FT /note="S->A: No effect on sumoylation; when associated with
FT 6-A--A-9; A-237; A-320 and A-521."
FT /evidence="ECO:0000269|PubMed:22493429"
FT MUTAGEN 258
FT /note="K->R: No effect on protein stability, inhibited
FT sumoylation, increased transcriptional activity; when
FT associated with R-229."
FT /evidence="ECO:0000269|PubMed:22493429"
FT MUTAGEN 320
FT /note="S->A: No effect on sumoylation; when associated with
FT 6-A--A-9; A-237; A-243 and A-521."
FT /evidence="ECO:0000269|PubMed:22493429"
FT MUTAGEN 521
FT /note="S->A: No effect on sumoylation; when associated with
FT 6-A--A-9; A-237; A-243 and A-320."
FT /evidence="ECO:0000269|PubMed:22493429"
FT CONFLICT 180..186
FT /note="VKDKEEK -> KKEITFI (in Ref. 6; AAA03159)"
FT /evidence="ECO:0000305"
FT CONFLICT 496
FT /note="G -> A (in Ref. 1; AAC24209)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 553 AA; 56940 MW; 3CDB14F69AA2F217 CRC64;
MQARYSVSSP NSLGVVPYLG GEQSYYRAAA AAAGGGYTAM PAPMSVYSHP AHAEQYPGSM
ARAYGPYTPQ PQPKDMVKPP YSYIALITMA IQNAPDKKIT LNGIYQFIMD RFPFYRDNKQ
GWQNSIRHNL SLNECFVKVP RDDKKPGKGS YWTLDPDSYN MFENGSFLRR RRRFKKKDAV
KDKEEKGRLH LQEPPPPQAG RQPAPAPPEQ AEGSAPGPQP PPVRIQDIKT ENGTCPSPPQ
PLSPAAALGS GSAATVPKIE SPDSSSSSLS SGSSPPGSLP SARPLSLDAA EPAPPPQPAP
PPHHSQGFSV DNIMTSLRGS PQGSAAELGS GLLASAAASS RAGIAPPLAL GAYSPGQSSL
YSSPCSQSSS AGSSGGGGGG GGGGGGSSSA AGTGGAATYH CNLQAMSLYA AGERGGHLQG
PAGGAGSAAV DDPLPDYSLP PATSSSSSSL SHGGGGQEAS HHPASHQGRL TSWYLNQAGG
DLGHLASAAA AAAAAGYPGQ QQNFHSVREM FESQRIGLNN SPVNGNSSCQ MAFPASQSLY
RTSGAFVYDC SKF
