Nodal is a 13 kDa member of the TGF-beta superfamily of molecules (1-3). Its name derives from the fact that it is expressed in the primitive node of the developing embryo. In human, it is synthesized as a 347 amino acid (aa) preproprecursor that contains a 26 aa signal sequence, a 211 aa prodomain, and a 110 aa mature region (4, 5). Consistent with its TGF-beta superfamily membership, it exists as a disulfide-linked homodimer and would be expected to demonstrate a cysteine-knot motif (1, 5, 6). Mature human Nodal is 99%, 98%, 96% and 98% aa identical to mature canine, rat, bovine and mouse Nodal, respectively. Nodal signals through two receptor complexes, both of which contain members of the TGF-beta family of Ser/Thr kinase receptors. The first receptor complex is composed of ActRIB/ALK4 and ActRIIB. Nodal interaction with the ligand-binding subunit ALK4 requires the participation of fucosylated Cripto, a member of the EGF-CFC gene family. The second complex is composed of ALK7 and ActRIIB, and does not require Cripto interaction (7-9). Nodal signaling is regulated by a number of inhibitors. Nodal is reported to form nonsignaling disulfide-linked heterodimers with BMP-3, -4 and -7 (2, 6). There are also at least three secreted factors that block Nodal activation of its receptor. The first is Cerberus, a member of the DAN family of proteins. The last two are TGF-beta family members named Lefty-A and B (2, 11). The exact mechanisms employed are unclear, but Leftys are apparently induced by nodal and can work at a considerable distance from their origin (2). Nodal is known to induce both mesoderm and endoderm, participate in anterior-posterior positioning, and through ALK7, induce apoptosis in susceptible cell populations (2, 8, 12).