MUTATION OF THE MOUSE HEPATOCYTE NUCLEAR FACTOR FORKHEAD HOMOLOG-4 GENE RESULTS IN AN ABSENCE OF CILIA AND RANDOM LEFT-RIGHT ASYMMETRY

Winged helix transcription factors play important roles in cellular di fferentiation 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 e xpression of HFH-4 was detected in hflt-4(-/-) mice by RNA blot analys is, in situ hybridization, or RT-PCR. hfh-4(-/-) mice were noted to ha ve abnormalities of organ situs consistent with random determination o f left-right asymmetry. In addition, a complete absence of cilia was n oted in hfh-4(-/-) mice. The hfh-4 gene is thus essential for nonrando m determination of left-right asymmetry and development of ciliated ce lls. Homozygous mutant mice also exhibited prenatal and postnatal grow th failure, perinatal lethality and, in some cases, hydrocephalus. RT- PCR revealed an absence of left-right dynein (lrd) expression in the e mbryonic lungs of hfh-4(-/-) mice, suggesting that HFH-4 may act by re gulating expression of members of the dynein family of genes. The abno rmalities in ciliary development and organ situs in hfh-4(-/-) mice ar e similar to those observed in human congenital syndromes such as Kart agener syndrome. Targeted mutation of hfh-4 thus provides a model for elucidating the mechanisms regulating ciliary development and determin ation of left-right asymmetry.