Abstract
Zebrafish Gdf3 (Dvr1) is a member of the TGFβ superfamily of cell signaling ligands that includes Xenopus 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 gdf3 RNA, demonstrating that Gdf3 is required only early in development, beyond which mutants are viable and fertile. Gdf3 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 gdf3 mutants, indicating that Gdf3 functions at the same pathway step as Nodal. Targeting gdf3 and ndr2 RNA to specific lineages indicates that exogenous gdf3 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.
Highlights
Nodal, a member of the TGFb superfamily of cell-cell signaling ligands, is essential in the establishment of vertebrate axis patterning, both the primary embryonic axis during gastrulation and the orthogonal left-right (LR) asymmetries in heart, brain and gut development. vg1, another member of the TGFb family, was prototypically described as the first-known regionally localized RNA in a vertebrate oocyte, localized to the vegetal pole of the egg, and subsequently in early embryos (Rebagliati et al, 1985)
High resolution melt analysis (HRMA) (Parant et al, 2009) was used to screen for mutations in genomic DNA from embryos of G0 founders and later, from fin clips from adults derived from those founders (Figure 1B)
Embryos generated from fertilization of a gdf3-deficient mutant egg by a wildtype gdf3+ sperm display the same embryonic lethal MZgdf3 mutant phenotype as those fertilized with sperm from a homozygous gdf3- mutant father
Summary
A member of the TGFb superfamily of cell-cell signaling ligands, is essential in the establishment of vertebrate axis patterning, both the primary embryonic axis during gastrulation and the orthogonal left-right (LR) asymmetries in heart, brain and gut development. vg, another member of the TGFb family, was prototypically described as the first-known regionally localized RNA in a vertebrate oocyte, localized to the vegetal pole of the egg, and subsequently in early embryos (Rebagliati et al, 1985). A member of the TGFb superfamily of cell-cell signaling ligands, is essential in the establishment of vertebrate axis patterning, both the primary embryonic axis during gastrulation and the orthogonal left-right (LR) asymmetries in heart, brain and gut development. Vg, another member of the TGFb family, was prototypically described as the first-known regionally localized RNA in a vertebrate oocyte, localized to the vegetal pole of the egg, and subsequently in early embryos (Rebagliati et al, 1985). At later stages of development, overexpression or grafts into lateral plate mesoderm that activate TGFb family member Xenopus Nodal (Xnr1) in right lateral plate can invert asymmetry (Ohi and Wright, 2007). Similar to vg in Xenopus, gdf RNA and protein are abundantly stored in the oocyte and early embryo before zygotic gene activation in zebrafish (Helde and Grunwald, 1993; Peterson et al, 2013).
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