Dataset Information

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

ABSTRACT: Zebrafish Gdf3 (Dvr1) is a member of the TGF? 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 TGF? 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.

SUBMITTER: Bisgrove BW

PROVIDER: S-EPMC5745076 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Bisgrove Brent W BW Su Yi-Chu YC Yost H Joseph HJ

eLife 20171115

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 refrac ...[more]

PMID: 29140249

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Project description:Embryonic axis formation in vertebrates is initiated by the establishment of the dorsal Nieuwkoop blastula organizer, marked by the nuclear accumulation of maternal ?-catenin, a transcriptional effector of canonical Wnt signaling. Known regulators of axis specification include the canonical Wnt pathway components that positively or negatively affect ?-catenin. An involvement of G-protein coupled receptors (GPCRs) was hypothesized from experiments implicating G proteins and intracellular calcium in axis formation, but such GPCRs have not been identified. Mobilization of intracellular Ca(2+) stores generates Ca(2+) transients in the superficial blastomeres of zebrafish blastulae when the nuclear accumulation of maternal ?-catenin marks the formation of the Nieuwkoop organizer. Moreover, intracellular Ca(2+) downstream of non-canonical Wnt ligands was proposed to inhibit ?-catenin and axis formation, but mechanisms remain unclear. Here we report a novel function of Ccr7 GPCR and its chemokine ligand Ccl19.1, previously implicated in chemotaxis and other responses of dendritic cells in mammals, as negative regulators of ?-catenin and axis formation in zebrafish. We show that interference with the maternally and ubiquitously expressed zebrafish Ccr7 or Ccl19.1 expands the blastula organizer and the dorsoanterior tissues at the expense of the ventroposterior ones. Conversely, Ccr7 or Ccl19.1 overexpression limits axis formation. Epistatic analyses demonstrate that Ccr7 acts downstream of Ccl19.1 ligand and upstream of ?-catenin transcriptional targets. Moreover, Ccl19/Ccr7 signaling reduces the level and nuclear accumulation of maternal ?-catenin and its axis-inducing activity and can also inhibit the Gsk3? -insensitive form of ?-catenin. Mutational and pharmacologic experiments reveal that Ccr7 functions during axis formation as a GPCR to inhibit ?-catenin, likely by promoting Ca(2+) transients throughout the blastula. Our study delineates a novel negative, Gsk3?-independent control mechanism of ?-catenin and implicates Ccr7 as a long-hypothesized GPCR regulating vertebrate axis formation.

Project description:Background:The clade of protostome animals known as the Spiralia (e.g., mollusks, annelids, nemerteans and polyclad flatworms) shares a highly conserved program of early development. This includes shared arrangement of cells in the early-stage embryo and fates of descendant cells into embryonic quadrants. In spiralian embryos, a single cell in the D quadrant functions as an embryonic organizer to pattern the body axes. The precise timing of the organizing signal and its cellular identity varies among spiralians. Previous experiments in the annelid Chaetopterus pergamentaceus Cuvier, 1830 demonstrated that the D quadrant possesses an organizing role in body axes formation; however, the molecular signal and exact cellular identity of the organizer were unknown. Results:In this study, the timing of the signal and the specific signaling pathway that mediates organizing activity in C. pergamentaceus was investigated through short exposures to chemical inhibitors during early cleavage stages. Chemical interference of the Activin/Nodal pathway but not the BMP or MAPK pathways results in larvae that lack a detectable dorsal-ventral axis. Furthermore, these data show that the duration of organizing activity encompasses the 16 cell stage and is completed before the 32 cell stage. Conclusions:The timing and molecular signaling pathway of the C. pergamentaceus organizer is comparable to that of another annelid, Capitella teleta, whose organizing signal is required through the 16 cell stage and localizes to micromere 2d. Since C. pergamentaceus is an early branching annelid, these data in conjunction with functional genomic investigations in C. teleta hint that the ancestral state of annelid dorsal-ventral axis patterning involved an organizing signal that occurs one to two cell divisions earlier than the organizing signal identified in mollusks, and that the signal is mediated by Activin/Nodal signaling. Our findings have significant evolutionary implications within the Spiralia, and furthermore suggest that global body patterning mechanisms may not be as conserved across bilaterians as was previously thought.

Dataset Information

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

Publications

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

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