A conserved domain of cfap298 governs left-right symmetry breaking in vertebrates

Abstract

Cfap298 is a highly conserved gene required for ciliary motility and dynein arm assembly, with known roles in left-right (LR) patterning in zebrafish and links to human ciliopathies. Here, we describe a Cfap298 mutant allele, Cfap298ΔΔS, which selectively disrupts LR axis establishment in mice. Mutant embryos display organ laterality defects and abnormal Nodal, Pitx2 and Lefty1 expression, consistent with an early disruption in LR symmetry breaking. LR asymmetry is established by leftward fluid flow in the node, generated by planar- polarized cilia. Although cfap298 mutations are reported to affect planar polarity, we did not observe changes in cilia position, length or CELSR1 localization within the node, suggesting that Cfap298ΔΔSfunctions at the level of cilia motility. Accordingly, cilia lining the trachea of Cfap298ΔΔSmutants fail to beat or beat incorrectly. Expression of the Cfap298ΔΔSvariant in zebrafish partially rescues body curvature defects but fails to rescue LR defects of cfap298 (kurly) loss-of-function mutants. These results confirm a conserved role for Cfap298 in mammalian LR patterning and identify a previously unreported region of CFAP298 with a conserved and essential role in cilia motility.