Nodal ligands are essential for the patterning of chordate embryos. Genetic
evidence indicates that EGF-CFC factors are required for Nodal signaling,
but the molecular basis for this requirement is unknown. We have investigat
ed the role of Cripto, an EGF-CFC factor, in Nodal signaling. We find that
Cripto interacts with the type I receptor ALK4 via the conserved CFC motif
in Cripto. Cripto interaction with ALK4 is necessary both for Nodal binding
to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal. W
e also find that Nodal can inhibit BMP signaling by a Cripto-independent me
chanism. Inhibition appears to be mediated by heterodimerization between No
dal and BMPs, indicating that antagonism between Nodal and BMPs can occur a
t the level of dimeric ligand production.