title: Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry.
abstract: Winged helix transcription factors play important roles in cellular differentiation and cell-specific gene expression. To define the role of the winged helix factor hepatocyte nuclear factor/forkhead homologue (HFH)-4, a targeted mutation was created in the mouse hfh-4 gene. No expression of HFH-4 was detected in hfh-4(-)/- mice by RNA blot analysis, in situ hybridization, or RT-PCR. hfh-4(-)/- mice were noted to have abnormalities of organ situs consistent with random determination of left-right asymmetry. In addition, a complete absence of cilia was noted in hfh-4(-)/- mice. The hfh-4 gene is thus essential for nonrandom determination of left-right asymmetry and development of ciliated cells. Homozygous mutant mice also exhibited prenatal and postnatal growth failure, perinatal lethality and, in some cases, hydrocephalus. 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. The abnormalities in ciliary development and organ situs in hfh-4(-)/- mice are similar to those observed in human congenital syndromes such as Kartagener syndrome. Targeted mutation of hfh-4 thus provides a model for elucidating the mechanisms regulating ciliary development and determination of left-right asymmetry.
authors.affiliation: The Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: H J
authors.initials: HJ
authors.lastname: Knowles
authors.forename: J L
authors.initials: JL
authors.lastname: Hebert
authors.forename: B P
authors.initials: BP
authors.lastname: Hackett
mesh_terms: D000015:Abnormalities, Multiple; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D019521:Body Patterning / Q000235:genetics*; D002831:Choroid Plexus / Q000196:embryology; D002923:Cilia / Q000235:genetics*; D004268:DNA-Binding Proteins; D004398:Dyneins / Q000096:biosynthesis; D005260:Female; D051858:Forkhead Transcription Factors; D006128:Growth; D051557:Hepatocyte Nuclear Factor 4; D007619:Kartagener Syndrome; D008168:Lung / Q000196:embryology; D008297:Male; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010057:Oviducts / Q000196:embryology; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013737:Testis / Q000196:embryology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D051557:Hepatocyte Nuclear Factor 4; D009687:Nuclear Proteins; D010750:Phosphoproteins; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; D004398:Dyneins