Nodal proteins are TGFβ-related, secreted signalling proteins that play essential roles in vertebrate embryonic development. In zebrafish, the Nodal-related factors Cyclops (Cyc) and Squint (Sqt) have overlapping functions during mesoderm induction and behave as short- and long-range morphogens, respectively. But what determines their different signalling activities? On , Tian and co-workers report that the pro-domain of Cyc (like other TGFβ-related proteins, Cyc contains a pro-domain and a mature domain) regulates its activity. Unlike other Nodal proteins, Cyc requires its pro-domain for its activity. They identify several pro-domain regions that regulate Cyc signalling activity, including a lysosome-targeting region that,by destabilising the Cyc precursor, restricts the distance over which Cyc acts. Finally, they report that a mutation in a conserved arginine in the Cyc pro-domain increases Cyc activity. This last observation hints at a possible aetiology for human congenital heterotaxia, a defect in left-right asymmetry caused by an identical mutation in human NODAL.
