Maternal Gdf3 is an obligatory cofactor in Nodal signaling for embryonic axis formation in zebrafish.

Abstract

Zebrafish Gdf3 (Dvr1) is a member of the TGFβ superfamily of cell signaling ligands that includes <i>Xenopus</i> Vg1 and mammalian Gdf1/3. Surprisingly, engineered homozygous mutants in zebrafish have no apparent phenotype. Elimination of Gdf3 in oocytes of maternal-zygotic mutants results in embryonic lethality that can be fully rescued with <i>gdf3</i> RNA, demonstrating that Gdf3 is required only early in development, beyond which mutants are viable and fertile. <i>Gdf3</i> mutants are refractory to Nodal ligands and Nodal repressor Lefty1. Signaling driven by TGFβ ligand Activin and constitutively active receptors Alk4 and Alk2 remain intact in <i>gdf3</i> mutants, indicating that Gdf3 functions at the same pathway step as Nodal. Targeting <i>gdf3</i> and <i>ndr2</i> RNA to specific lineages indicates that exogenous <i>gdf3</i> is able to fully rescue mutants only when co-expressed with endogenous Nodal. Together, these findings demonstrate that Gdf3 is an essential cofactor of Nodal signaling during establishment of the embryonic axis.