During gastulation, Nodal signalling on the left side of the ventral node establishes the left-right (LR) axis of the embryo, which controls the position of the internal organs. In mouse embryos, polycystic kidney disease 2(Pkd2), which encodes the Ca2+-activated channel polycystin 2 (PC2), is thought to activate left-side-specific Nodaltranscription. Now, Schottenfeld and colleagues reveal that LR patterning in zebrafish embryos also requires pkd2 but that here, pkd2restricts expression of the nodal gene southpaw(spaw) to the left half of the embryo (see p. 1605). They show that curly up (the zebrafish ortholog of Pkd2) mutants have LR defects in organ positioning that resemble human heterotaxia. But, whereas there is no activation of Nodal in the lateral plate mesoderm of mouse Pkd-/- embryos, spaw is bilaterally activated in curly up embryos, they report. Thus, although PC2 is involved in LR patterning in both zebrafish and mouse embryos, its function in this process might not be conserved, a result that calls into question the so-called two-cilia hypothesis for LR axis formation.