This gene encodes a member of theforkhead family of transcription factors. Similar genes in zebrafish and mouse have been shown to regulate the transcription of genes that control the production of motile cilia. The mouse ortholog also functions in the determination ofleft-right asymmetry.[5]
Primaryciliogenesis is FOXJ1 dependent and this transcription factor is required for motileciliated cell differentiation. The onset of FOXJ1 expression is indicative of cells fated to become motile ciliated cells.[13] Cells commit towards ciliogenesis prior to FOXJ1 activation. Activation promotesbasal body trafficking, docking at theapical membrane and subsequentaxoneme growth.[14] The protein p73 a member of thep53 protein family directly regulatesFOXJ1 and is a requirement for ciliated cell formation. The 10,000bp long transcription start site ofFOXJ1 features three sequence specific binding sites for p73.[15]
In mammalian cells, FOXJ1 has been shown to suppressNFκB, a key regulator in the immune response[16] and also inhibits the humoral response inB-cells. This occurs via regulation of an inhibitory component of NFκB called IκBβ and IL-6.[17]
FOXJ1 is expressed at various points during embryonic development in relation to teeth germination, enamel, oral and tongueepithelium formation, and formation of sub-mandibular salivary glands and hair follicles.[18] Absence of FOXJ1 expression decreasescalpastatin, an inhibitor of the proteasecalpain. Calpain dysregulation affects basal body anchoring to the apical cytoskeleton affecting axeonemal formation.[19] Expression of FOXJ1 is inhibited by IL-13.[20]
Viral infections of the respiratory system have been found to lower the expression of FOXJ1. This affects ciliogenesis and impactsmucocillary action.[21]
Studies into human breast tissue lines and primary breast tumors have observed that the geneFOXJ1 are aberrantly hypermethylated in primary tumors. This hypermethylation serves to silence production of the FOXJ1 protein and has been proposed as a potentially important event in tumor formation.[22]
FOXJ1 expression has been shown to be elevated in clear cell renal carcinoma patients and indicative of tumor stage,histological grade and tumor size. High expression of FOXJ1 in CRCC patients was associated with poor prognosis. There is potential for FOXJ1 to act as anoncogene marker for CRCC patients and has value as a therapeutic target.[23]
Axenfeld–Rieger syndrome patients have a point mutation inPITX2 a regulatory protein of theFOXJ1 gene. PITX2 alongsideLEF-1 andβ-Catenin regulateFOXJ1. FOXJ1 in turn interacts with PITX2 to form a positive feedback mechanism. In the PITX2 point mutant whilst able to bind with FOXJ1 lacks the ability to activate theFOXJ1 promoter, this results in improper oro-facial morphogenesis a factor in ARS.[24]
Mutations in this gene have been associated with an autosomal dominant syndrome that includeshydrocephalus and randomization of left/right body asymmetry.[25]
^Yu X, Ng CP, Habacher H, Roy S (December 2008). "Foxj1 transcription factors are master regulators of the motile ciliogenic program".Nature Genetics.40 (12):1445–53.doi:10.1038/ng.263.PMID19011630.S2CID205347068.
^Blatt EN, Yan XH, Wuerffel MK, Hamilos DL, Brody SL (August 1999). "Forkhead transcription factor HFH-4 expression is temporally related to ciliogenesis".American Journal of Respiratory Cell and Molecular Biology.21 (2):168–76.CiteSeerX10.1.1.317.9961.doi:10.1165/ajrcmb.21.2.3691.PMID10423398.
^Pelletier GJ, Brody SL, Liapis H, White RA, Hackett BP (March 1998). "A human forkhead/winged-helix transcription factor expressed in developing pulmonary and renal epithelium".The American Journal of Physiology.274 (3 Pt 1): L351–9.doi:10.1152/ajplung.1998.274.3.L351.PMID9530170.
^You Y, Huang T, Richer EJ, Schmidt JE, Zabner J, Borok Z, et al. (April 2004). "Role of f-box factor foxj1 in differentiation of ciliated airway epithelial cells".American Journal of Physiology. Lung Cellular and Molecular Physiology.286 (4): L650–7.doi:10.1152/ajplung.00170.2003.PMID12818891.S2CID17661686.
Turner J, Roger J, Fitau J, Combe D, Giddings J, Heeke GV, et al. (March 2011). "Goblet cells are derived from a FOXJ1-expressing progenitor in a human airway epithelium".American Journal of Respiratory Cell and Molecular Biology.44 (3):276–84.doi:10.1165/rcmb.2009-0304OC.PMID20539013.
Murphy DB, Seemann S, Wiese S, Kirschner R, Grzeschik KH, Thies U (March 1997). "The human hepatocyte nuclear factor 3/fork head gene FKHL13: genomic structure and pattern of expression".Genomics.40 (3):462–9.doi:10.1006/geno.1996.4587.PMID9073514.
Maiti AK, Bartoloni L, Mitchison HM, Meeks M, Chung E, Spiden S, et al. (2000). "No deleterious mutations in the FOXJ1 (alias HFH-4) gene in patients with primary ciliary dyskinesia (PCD)".Cytogenetics and Cell Genetics.90 (1–2):119–22.doi:10.1159/000015645.PMID11060460.S2CID21880343.
LeSimple P, van Seuningen I, Buisine MP, Copin MC, Hinz M, Hoffmann W, et al. (March 2007). "Trefoil factor family 3 peptide promotes human airway epithelial ciliated cell differentiation".American Journal of Respiratory Cell and Molecular Biology.36 (3):296–303.doi:10.1165/rcmb.2006-0270OC.PMID17008636.
Pelletier GJ, Brody SL, Liapis H, White RA, Hackett BP (March 1998). "A human forkhead/winged-helix transcription factor expressed in developing pulmonary and renal epithelium".The American Journal of Physiology.274 (3 Pt 1): L351–9.doi:10.1152/ajplung.1998.274.3.L351.PMID9530170.
Wu C, Ma MH, Brown KR, Geisler M, Li L, Tzeng E, et al. (June 2007). "Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening".Proteomics.7 (11):1775–85.doi:10.1002/pmic.200601006.PMID17474147.S2CID22474278.
