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Trb3 regulates LR axis formation in zebrafish embryos.

ABSTRACT: Tribless family proteins are pseudokinases that lack DFG (Asp-Phe-Gly) motif in the functional kinase domain, regulating Akt and BMP pathways, insulin metabolism, hypoxia, and ubiquitination. This report concerns expression patterns and functional roles of trb3 in zebrafish embryonic development. trb3 is evolutionarily well-conserved and located on zebrafish chromosome 11. Spatiotemporal expression studies show that trb3 transcripts are abundant throughout embryogenesis, but confined to mesendodermal cells during the late blastula phase. Over-expression of trb3 ventralizes the embryos while a knockdown of trb3 using morpholino alters positioning of the heart, liver, and pancreatic buds as well as gut looping. Furthermore, constitutive activation of TGF-signaling with TARAM-A* (TGF-related type I receptor) significantly increases the level of trb3 transcripts during the late blastula phase. Over-expression of trb3 reduces the level of smurf1 transcripts, a member of TGF-signaling. We thus propose that Trb3 governs left-right (LR) axis patterning as a component of TGF-signaling in vertebrate embryonic development.

SUBMITTER: Anuppalle M

PROVIDER: S-EPMC3887966 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Trb3 regulates LR axis formation in zebrafish embryos.

Anuppalle Mrudhula M Maddirevula Sateesh S Huh Tae-Lin TL Rhee Myungchull M

Molecules and cells 20131127 6

Tribless family proteins are pseudokinases that lack DFG (Asp-Phe-Gly) motif in the functional kinase domain, regulating Akt and BMP pathways, insulin metabolism, hypoxia, and ubiquitination. This report concerns expression patterns and functional roles of trb3 in zebrafish embryonic development. trb3 is evolutionarily well-conserved and located on zebrafish chromosome 11. Spatiotemporal expression studies show that trb3 transcripts are abundant throughout embryogenesis, but confined to mesendod ...[more]

PMID: 24292884

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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.

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Trb3 regulates LR axis formation in zebrafish embryos.

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Trb3 regulates LR axis formation in zebrafish embryos.

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