Gdf3 is required for robust Nodal signaling during germ layer formation and left-right patterning.

Jose L Pelliccia,Granton A Jindal,Rebecca D Burdine

doi:10.7554/elife.28635

Abstract

Vertebrate embryonic patterning depends on signaling from Nodal, a TGFβ superfamily member. There are three Nodal orthologs in zebrafish; southpaw directs left-right asymmetries, while squint and cyclops function earlier to pattern mesendoderm. TGFβ member Vg1 is implicated in mesoderm formation but the role of the zebrafish ortholog, Growth differentiation factor 3 (Gdf3), has not been fully explored. We show that zygotic expression of gdf3 is dispensable for embryonic development, while maternally deposited gdf3 is required for mesendoderm formation and dorsal-ventral patterning. We further show that Gdf3 can affect left-right patterning at multiple stages, including proper development of regional cell morphology in Kupffer's vesicle and the establishment of southpaw expression in the lateral plate mesoderm. Collectively, our data indicate that gdf3 is critical for robust Nodal signaling at multiple stages in zebrafish embryonic development.

Highlights

Transforming Growth Factor-b (TGFb) superfamily proteins Nodal and Bone Morphogenetic Protein (Bmp) are secreted ligands that play essential roles in development, including maintaining pluripotency of embryonic stem cells and in the patterning of the early embryo (Morikawa et al, 2016)
The amount of gdf3 mRNA diminishes rapidly through the blastula and gastrula stages and disappears by approximately 90% epiboly (Helde and Grunwald, 1993). This is followed by the return of expression in a tissue-restricted manner starting at the late bud stage and progressing into somitogenesis, when expression is observed in the lateral plate mesoderm (LPM) and in cells around Kupffer’s vesicle (KV) (Figure 1A) (Peterson et al, 2013)
Nodal can signal independently of Growth differentiation factor 3 (Gdf3), target genes required for head and trunk mesendoderm are not activated without Gdf3 unless Nodal is overexpressed beyond physiological levels

Summary

Introduction

Transforming Growth Factor-b (TGFb) superfamily proteins Nodal and Bone Morphogenetic Protein (Bmp) are secreted ligands that play essential roles in development, including maintaining pluripotency of embryonic stem cells and in the patterning of the early embryo (Morikawa et al, 2016). The well-conserved Nodal ligand binds to a heteromeric complex of receptors that phosphorylate Smad2/3, which enables its association with Smad (Hata and Chen, 2016). This Smad complex interacts with transcription factors in the nucleus to activate the expression of target genes. The Bmp signaling pathway shares some common components with the Nodal pathway except Bmp binds to a different heteromeric complex of receptors that phosphorylates Smad1/5/8, enabling their association with Smad and activating Bmp-specific target genes (Hata and Chen, 2016).

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