Fig 6. Model for Generation of Left Isomerism in Ccdc40 versus Shh pathway mutants.

In 1-somite stage wild type embryos, Cerl2 expression (green) becomes asymmetric with reduced expression on the left side of the node in response to fluid flow. With reduced expression of its antagonist on the left, Nodal activity and expression (dark blue) increases on the left side and decreases on the right. In 2-somite stage wild type embryos, Nodal induce Nodal expression in the L-LPM and by the 3-somite stage robust expression of Nodal along with Lefty1 and Lefty2 (light blue) is detected in the L-LPM and Lefty1 in the midline (light blue). In 4-somite stage embryos Nodal expression is reduced but Lefty1 and Lefty2 are strongly expressed in the L-LPM. Lefty1 expression in the midline and Cerl2 around the node inhibits Nodal signaling in the R-LPM. With lack of nodal flow in Ccdc40^lnks and other cilia mutants with intact Shh signaling, Cerl2 and Nodal expression remains symmetric. Continued Cerl2 mediated antagonism of Nodal results in reduced Nodal signaling around the node and Nodal and Lefty1/2 expression in the LPM is delayed till the 3- and 4-somite stages, respectively. In a proportion of embryos where symmetry is not broken, Nodal signaling is reduced and bilateral. This is in contrast to IFT mutants with defects in Shh signaling. In these embryos, Nodal signaling is robustly induced bilaterally compounded by failure to activate the midline barrier.