Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry

J Clin Invest. 1998 Sep 15;102(6):1077-82. doi: 10.1172/JCI4786.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abnormalities, Multiple
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Body Patterning / genetics*
  • Choroid Plexus / embryology
  • Cilia / genetics*
  • DNA-Binding Proteins*
  • Dyneins / biosynthesis
  • Female
  • Forkhead Transcription Factors
  • Growth
  • Hepatocyte Nuclear Factor 4
  • Kartagener Syndrome
  • Lung / embryology
  • Male
  • Mice
  • Mutation*
  • Nuclear Proteins / genetics
  • Oviducts / embryology
  • Phosphoproteins / deficiency*
  • Phosphoproteins / genetics
  • Sequence Homology, Amino Acid
  • Testis / embryology
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Hepatocyte Nuclear Factor 4
  • Nuclear Proteins
  • Phosphoproteins
  • Tcfl4 protein, mouse
  • Transcription Factors
  • Dyneins