Ciliogenesis and left-right axis defects in forkhead factor HFH-4-null mice

Cilia have been classified as sensory or motile types on the basis of funct ional and structural characteristics; however, factors important for regula tion of assembly of different cilia types are not well understood. Hepatocy te nuclear factor-3/forkhead homologue 4 (HFH-4) is a winged helix/forkhead transcription factor expressed in ciliated cells of the respiratory tract, oviduct, and ependyma in late development through adulthood. Targeted dele tion of the Hfh4 gene resulted in defective ciliogenesis in airway epitheli al cells and randomized left-right asymmetry so that half the mice had situ s inversus. In HFH-4-null mice, classic motile type cilia with a 9 + 2 micr otubule ultrastructure were absent in epithelial cells, including those in the airways. In other organs, sensory cilia with a 9 + 0 microtubule patter n, such as those on olfactory neuroepithelial cells, were present. Ultrastr uctural analysis of mutant cells with absent 9 + 2 cilia demonstrated that defective ciliogenesis was due to abnormal centriole migration and/or apica l membrane docking, suggesting that HFH-4 functions to direct basal body po sitioning or anchoring. Evaluation of wild-type embryos at gestational days 7.0 to 7.5 revealed Hfh4 expression in embryonic node cells that have mono cilium, consistent with a function for this factor at the node in early det ermination of left-right axis. Analysis of the node of HFH-4 mutant embryos revealed that, in contrast to absent airway cilia, node cilia were present . These observations indicate that there are independent regulatory pathway s for node ciliogenesis compared with 9 + 2 type ciliogenesis in airways, a nd support a central role for HFH-4 in ciliogenesis and left-right axis for mation.