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Leftward fluid flow in the mouse node is generated by cilia and is critical for initiating asymmetry of the left-right axis.  Coiled-coil domain containing-40  ( Ccdc40 ) plays an evolutionarily conserved role in the assembly of motile cilia and establishment of the left-right axis. Approximately one-third of  Ccdc40   lnks   mutant embryos display situs defects and here we investigate the underlying mechanism.  Ccdc40   lnks   mutants show delayed induction of markers of the left-lateral plate mesoderm (L-LPM) including  Lefty1 ,  Lefty2  and  Nodal . Consistent with defective cilia motility compromising fluid flow across the node, initiation of asymmetric perinodal  Cerberus like-2  ( Cerl2 ) expression is delayed and then randomized. This is followed by delayed and then randomized asymmetric  Nodal  expression around the node. We propose a model to explain how left isomerism arises in a proportion of  Ccdc40   lnks   mutants. We postulate that with defective motile cilia,  Cerl2  expression remains symmetric and Nodal is antagonized equally on both sides of the node. This effectively reduces Nodal activation bilaterally, leading to reduced and delayed activation of Nodal and its antagonists in the LPM. This model is further supported by the failure to establish  Nodal  expression in the left-LPM with reduced Nodal gene dosage in  Ccdc40   lnks/lnks  ; Nodal   LacZ/+   mutants causing a predominance of right not left isomerism. Together these results suggest a model where cilia generated fluid flow in the node functions to ensure robust Nodal activation and a timely left-sided developmental program in the LPM.

Mechanism for generation of left isomerism in Ccdc40 mutant embryos