Mouse lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation

Mammalian lefty and zebrafish antivin form a subgroup of the TGF beta super family. We report that mouse mutants for lefty2 have an expanded primitive! streak and form excess mesoderm, a phenotype opposite to that of mutants f or the TGF beta gene nodal. Analogously, overexpression of Antivin or Lefty 2 in zebrafish embryos blocks head and trunk mesoderm formation, a phenotyp e identical to that of mutants caused by loss of Nodal signaling. The lefty 2 mutant phenotype is partially suppressed by heterozygosity for nodal. Sim ilarly, the effects of Antivin and Lefty2 can be suppressed by overexpressi on of the nodal-related genes cyclops and squint or the extracellular domai n of ActRIIB. Expression of antivin is dependent on Nodal signaling, reveal ing a feedback loop wherein Nodal signals induce their antagonists Lefty2 a nd Antivin to restrict Nodal signaling during gastrulation.