Disease relevance of Foxj1

• In Foxj1 knockout mice, half show situs solitus while the other half show situs inversus, which means a random determination of the left-right axis [1].
• Similar changes in epithelial cell Foxj1 expression were also observed in human paramyxoviral respiratory infection [2].
• Instead, CD2-Foxj1 transgenic mice exhibited a peripheral T cell lymphopenia, associated with an accumulation of mature single-positive thymocytes [3].
• Transfection of plasmids containing Hfh4 5' flanking sequence linked to a reporter gene results in promoter activity in lung epithelial cells but not in epithelial-like fibrosarcoma cells, suggesting that this 5' flanking sequence can function as a promoter with the proper cell-type specificity [4].
• No deleterious mutations in the FOXJ1 (alias HFH-4) gene in patients with primary ciliary dyskinesia (PCD) [5].

High impact information on Foxj1

• One of these mammalian family members, HNF-3/fork head homolog-4 (HFH-4), was isolated by PCR amplification of rodent brain cDNA and exhibits abundant expression in the adult bronchiolar epithelium [6].
• The winged helix transcription factor HFH-4 is expressed during choroid plexus epithelial development in the mouse embryo [6].
• We used in vitro DNA-binding site selection with recombinant HFH-4 protein and determined that the HFH-4 protein recognizes the DNA consensus sequences HWDTGTTTGTTTA or KTTTGTTGTTKTW (where H is not G, W is A or T, D is not C, and K is G or T) [6].
• In support of these binding studies, cotransfection assays show that HFH-4 potentiates expression of the HNF-3alpha and clara cell secretory protein promoter regions [6].
• The unique temporal and spatial pattern of HFH-4 gene expression in the developing lung defines this protein as a marker for the initiation of bronchial epithelial cell differentiation and suggests that it may play an important role in cell fate determination during lung development [7].

Biological context of Foxj1

• The forkhead transcription factor Foxj1 inhibits spontaneous autoimmunity, in part by antagonizing NF-kappaB activation in T cells [8].
• Thus, Foxj1 restrains B cell activation and the maturation of humoral responses, demonstrating a critical role for at least this forkhead transcription factor in the regulation of B lymphocyte homeostasis [8].
• Foxj1 is an f-box transcription factor expressed in ciliated cells and shown to be required for cilia formation by gene deletion in a mouse model [9].
• Foxj1 regulates asymmetric gene expression during left-right axis patterning in mice [10].
• We thus made Foxj1/inv double mutant mice and analyzed their phenotype [1].

Anatomical context of Foxj1

• Foxj1 regulates basal body anchoring to the cytoskeleton of ciliated pulmonary epithelial cells [11].
• To define the role of Foxj1 in ciliogenesis, microarray analysis was performed to identify differentially expressed genes in the pulmonary epithelium of foxj1(+/+) and foxj1(-/-) mice [11].
• HNF-3/forkhead homologue 4 (HFH-4), a transcription factor of the winged helix/forkhead family, is expressed in various tissues including lung, brain, oviduct, testis, and embryonic kidney [12].
• A cDNA encoding a member of this family of proteins, termed hepatocyte nuclear factor/forkhead homologue 4 (HFH-4), has been isolated from rat lung and rat testis cDNA libraries [7].
• This pattern of HFH-4 gene expression during the early stages of differentiation of haploid germ cells suggests that HFH-4 may play a role in regulating stage-specific gene expression and cell-fate determination during lung development and in spermatogenesis [7].

Regulatory relationships of Foxj1

• In vitro, Sox17 inhibited Sftpc and enhanced Foxj1 promoter activity, consistent with its expression in proximal airway cells [13].
• Previous studies suggest that the forkhead transcription factor Foxj1 inhibits spontaneous autoimmunity in part by antagonizing NF-kappaB activation [3].

Other interactions of Foxj1

• Foxj1 is required for apical localization of ezrin in airway epithelial cells [14].
• Restraint of B cell activation by Foxj1-mediated antagonism of NF-kappa B and IL-6 [8].
• Expanded expression of the proximal epithelial cell markers CC10 and HFH-4 (Foxj1) was observed in the distal regions of transgenic lungs [15].
• Atypical cuboidal or columnar cells lined the lung periphery of SP-C/HFH-4 transgenic mice [12].
• The presence of HFH-4 and beta-tubulin IV in TTF-1 gene-targeted mice demonstrates that differentiation of ciliated epithelium does not require TTF-1 [16].

Analytical, diagnostic and therapeutic context of Foxj1

• Foxj1 deficiency resulted in multiorgan systemic inflammation, exaggerated Th1 cytokine production, and T cell proliferation in autologous mixed lymphocyte reactions [17].
• The morphology of the lungs from SP-C/HFH-4 embryos (day 18 postconception) was distinctly abnormal, and the severity of the alterations correlated with the level of transgene expression as detected by in situ hybridization [12].
• RT-PCR revealed an absence of left-right dynein (lrd) expression in the embryonic lungs of hfh-4(-)/- mice, suggesting that HFH-4 may act by regulating expression of members of the dynein family of genes [18].
• HNF-3/forkhead homologue-4 (HFH-4), a transcription factor of the winged-helix/forkhead family, was detected by immunohistochemistry in tissue of the developing mouse [16].

References