The zebrafish mutation curly up (cup) affects the zebrafish ortholog of polycystic kidney disease 2, a gene that encodes the Ca(2+)-activated non-specific cation channel, Polycystin 2. We have characterized two alleles of cup, both of which display defects in organ positioning that resemble human heterotaxia, as well as abnormalities in asymmetric gene expression in the lateral plate mesoderm (LPM) and dorsal diencephalon of the brain. Interestingly, mouse and zebrafish pkd2(-/-) mutants have disparate effects on nodal expression. In the majority of cup embryos, the zebrafish nodal gene southpaw (spaw) is activated bilaterally in LPM, as opposed to the complete absence of Nodal reported in the LPM of the Pkd2-null mouse. The mouse data indicate that Pkd2 is responsible for an asymmetric calcium transient that is upstream of Nodal activation. In zebrafish, it appears that pkd2 is not responsible for the activation of spaw transcription, but is required for a mechanism to restrict spaw expression to the left half of the embryo. pkd2 also appears to play a role in the propagation of Nodal signals in the LPM. Based on morpholino studies, we propose an additional role for maternal pkd2 in general mesendoderm patterning.