Cortez, M.; Young, C. B.; Little, K. A.; Grimes, D. T.; Devenport, D.; Burdine, R. D.

Cfap298 is a highly conserved gene required for ciliary motility and dynein arm assembly. It plays a known role in Left-Right (LR) patterning in zebrafish and is linked to human ciliopathies. Here we describe a new Cfap298 mutant allele, Cfap298{Delta}3aa, which selectively interferes with LR axis establishment in mice. Mutant embryos display a range of laterality defects including situs solitus, situs inversus, and situs ambiguous, as indicated by abnormal heart, lung, and stomach positioning. At embryonic day 8.5, mutant embryos display abnormal Nodal, Pitx2, and Lefty1 expression patterns in the lateral plate mesoderm and midline, consistent with an early disruption in LR symmetry breaking. In mice, LR asymmetry is established by leftward fluid flow in the node, generated by planar-polarized cilia. Although cfap298 mutations are reported to affect cell polarity, we did not observe changes in cilia position, length, or planar cell polarity protein localization within the node, suggesting that Cfap298{Delta}3aa functions at the level of cilia motility. Consistently, motile cilia lining the trachea of Cfap298{Delta}3aa mutants fail to beat. Expression of the Cfap298{Delta}3aa variant in zebrafish fails to rescue the LR defects of cfap298 (kurly) loss-of-function mutants. These results confirm that Cfap298 functions in LR axis formation in mammals and uncover a novel region of CFAP298 protein with a conserved and essential role in cilia motility.