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FLASH GENE
Symbol FOXC1 contributors: shn/npt/pgu - updated : 20-03-2016
HGNC name forkhead box C1
HGNC id 3800
Corresponding disease
AN aniridia
AXRI Axenfeld-Rieger syndrome, type 3
DEL6PD chromosome 6p subtelomeric deletion syndrome
DWM2 Dandy-Walker malformation-linked locus 2
IRID1 Iridogoniodysgenesis, type 1
Location 6p25.3      Physical location : 1.610.680 - 1.614.127
Synonym name
  • forkhead-related activator 3
  • transcription factor-like 7
  • myeloid factor-delta
  • forkhead/winged helix-like transcription factor 7
  • Synonym symbol(s) FREAC3, FKHL7, ARA, IGDA, IHG1, IRID1, ARA, RIEG3, FREAC-3
    DNA
    TYPE functioning gene
    STRUCTURE 3.45 kb     1 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map pter - D6S1600 - D6S344 - FOXC1- D6S1617 - D6S1713 - cen
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    1 - 3452 57 553 - 2009 19668217
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly Homo sapiens
    Digestiveliver   lowly
    Hearing/Equilibriumearinnercochlea predominantly
    Nervousbrain     Homo sapiens
    Visualeyeanterior segment  highly
     eyeretina  highly
     eyeuveachoroid highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone    Homo sapiens
    Epithelialbarrier liningretinal pigment epithelium (RPE) highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, fetal
    Text fetal tissues, eye
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a forkhead domain with a FH region and a winged helix region which is necessary for normal DNA-binding and transactivation functions
  • two loops-wings on the C-terminal side of helix-turn-helix homeo domain
  • two polymorphic polyglycine tracts
  • SC motifs mediating the inhibitory function by serving as sites for SUMOylation, revealing a novel mechanism for acute and reversible regulation of FOXC1/C2 function
  • mono polymer monomer
    HOMOLOGY
    interspecies homolog to Drosophila homeo forkhead DNA binding domain
    ortholog to Foxc1, Mus musculus
    ortholog to FOXC1, Pan troglodytes
    ortholog to rCG_44068, Rattus norvegicus
    Homologene
    FAMILY
  • forkhead family of transcription factors
  • CATEGORY DNA associated , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • embryonic transcriptional regulator
  • regulation of embryonic ocular (anterior chamber) development
  • important regulator of the chemotactic motility of endothelial cells through the induction of CXCR4 expression
  • playing an an important role in the direct regulation of the FGF19-FGFR4-MAPK pathway to promote both the development and maintenance of anterior segment structures within the eye
  • required for the prepatterning of anterior and posterior domains in the presumptive somites through a putative Notch/Delta/Mesp regulatory loop
  • functions as a tumor suppressor through TGF-beta1mediated signals
  • essential mediator of cellular homeostasis in the eye and indicate that a decreased resistance to oxidative stress may underlie Axenfeld-Rieger-glaucoma pathogenesis
  • playing a previously unrecognized role for mesenchyme-neuroepithelium interactions in the mid-hindbrain during early embryogenesis
  • FOXC1 and FOXC2 are forkhead transcription factors that play essential roles during development and physiology
  • FOXC1 occupies a conserved element in the MSX2 promoter
  • sets potentially a threshold for the BMP-dependent activation of MSX2, thus controlling the differentiation of osteogenic precursor cells and the rate and pattern of calvarial bone development
  • is a specific transcriptional regulator essential for development and maintenance of the mesenchymal niches for haematopoietic stem and progenitor cells
  • essential role for FOXC1 in the early stage of vascular formation in the telencephalon
  • FOXC1, GMDS, FOXF2, and FOXQ1 may represent loci for enhancer-driven changes in gene expression that could affect the developing embryo
  • encodes a developmental transcription factor required for brain, heart, and eye development
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS development
    text ocular development
    PATHWAY
    metabolism
    signaling sensory transduction/vision
  • a FOXC1/MSX2 regulatory network functions in the initial stages of osteoblast differentiation
  • FOXC1 - FGF8 signaling regulates mammalian jaw patterning, providing a mechanistic basis for the pathogenesis of syngnathia
  • a component
    INTERACTION
    DNA binding
    RNA
    small molecule
    protein
  • actin-binding protein filamin A, FLNA
  • pre-B-cell leukemia homeobox 1, PBX1
  • TGFB1 (for negative regulation of cell growth)
  • functional interaction between FOXC1 and PITX2A underlies the sensitivity to FOXC1 gene dosage in Axenfeld-Rieger syndrome and related anterior segment dysgeneses
  • regulates the expression of FOXO1A and binds to a conserved element in the FOXO1A promoter
  • direct target of FGF19 in the eye (FOXC1 positively regulates FGF19 expression in corneal and periocular mesenchymal cells)
  • role in development of the skull and cerebral cortex
  • regulates the expression of FOXO1A and binds to a conserved element in the FOXO1A promoter
  • MMP7 is a key downstream effector of FOXC1-mediated invasiveness in breast cancer
  • FOXC1 regulates the expression of RAB3GAP1, RAB3GAP2 and SNAP25, three genes with central roles in both exocytosis and endocytosis, responsible for extracellular trafficking
  • FOXC1 promotes colorectal cancer metastasis through transactivating ITGA7 and FGFR4 expression
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) AXRI , DEL6PD , DWM2 , AN , IRID1
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   deletion    
    in endometrial and ovarian cancer
    constitutional   deletion    
    or duplication in eye anterior segment abnormalities, glaucoma
    constitutional somatic mutation      
  • four potentially pathogenic FOXC1 mutations causing amino acid substitutions (P79R, Y115S, G149D, and M161V)
  • responsible for a significant profortion of Axenfeld-Rieger malformation in Germany
  • constitutional germinal mutation      
    associated white matter hyperintensities, dilated perivascular spaces, and lacunar infarction, by patients with cerebral small-vessel disease (CSVD)
    tumoral     --over  
    is associated with poor prognosis in pancreatic ductal adenocarcinoma
    constitutional       loss of function
    altered FOXC1 function associated to cerebral small-vessel disease (CSVD)
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerendocrinepancreas
    may provide an opportunity for developing a novel therapeutic target as well as a prognostic marker in PDA (pancreatic ductal adenocarcinoma)
    ANIMAL & CELL MODELS
  • Foxc1 (+/-)mice have anterior segment abnormalities: small or absent Schlemm's canal, aberrantly developed trabecular meshwork, iris hypoplasia, severely eccentric pupils and displaced Schwalbe's line
  • embryos lacking Foxc1 die pre- or perinatally including defects in the axial skeleton and cardiovascular system
  • compound Foxc1; Foxc2 homozygotes die earlier and with much more severe defects than single homozygotes alone. They have profound abnormalities in the first and second branchial arches, and the early remodeling of blood vessels
  • mice carrying the null-mutated Foxc1 gene frequently develop an anomalous double collecting system
  • hypomorphic mouse allele for Foxc1 (Foxc1(hith)) survives into adulthood which embryonic and postnatal histological analyses indicate that diminished Foxc1 protein expression in all three layers of meningeal cells leading to cortical and skull defects, detachment of radial glial endfeet, marginal zone heterotopias and cortical dyslamination
  • Foxc1-null mice have embryonic abnormalities of the rhombic lip due to loss of mesenchyme-secreted signaling molecules with subsequent loss of Atoh1 expression in vermis
  • expression of the Msx2 homeobox gene, an essential regulator of calvarial bone development is absent in the skull mesenchymal progenitors of Foxc1 mutant mice