Abstract
Author SummaryThe arrangement of dorsoventral (back to belly) and anteroposterior (head to tail) embryonic structures is specified early during animal embryogenesis. In vertebrates, this process of axes formation is initiated by β-catenin, a transcriptional effector of Wnt signaling, which marks the prospective dorsal side. Thus far, all known regulators of axis specification that affect β-catenin include components of the Wnt pathway. G protein-coupled receptors (GPCRs), as well as Ca2+ signaling, have also been hypothesized to inhibit β-catenin and axis formation, however the identity of such GPCRs has remained unclear. Here, we identify two novel regulators of axis formation: the zebrafish Ccr7 chemokine GPCR and one of its ligands, Ccl19.1, both of which are uniformly expressed in the early zebrafish embryo. We show that reducing the expression of Ccr7 or Ccl19.1 increases β-catenin levels and also the dorsoanterior tissues at the expense of the ventroposterior ones. Conversely, an excess of Ccr7 or Ccl19.1 lowers β-catenin levels and limits axis formation. Further experiments show that Ccr7 acts upstream of β-catenin transcriptional targets. Our study delineates a novel mechanism for the negative control of β-catenin, whereby Ccr7 increases β-catenin degradation in a Gsk3b-independent manner, likely by promoting Ca2+ signaling throughout the embryo. In a new model of axis specification we propose that Ccr7 acts as a long-hypothesized GPCR that provides a global inhibition of β-catenin to ensure the precise formation of embryonic axes.
Highlights
In vertebrate development, a cascade of inductive events patterns the dorsoventral (DV) and anteroposterior (AP) embryonic axes through the establishment of the embryonic organizing centers
At 11 hpf (Figure S1C) and 27 hpf, the embryos injected with MO1-ccr7 displayed a range of dorsalized phenotypes [39], including trunk and tail truncations (Class C4–C5; Figure 1Ab; all experimental numbers are provided in figure legends) or tail and ventral tail fin deficiencies (Class C3; Figure 1Ab9)
Since canonical Wnt, Bone morphogenetic protein (BMP), Nodal, FGF, and retinoic acid signaling pathways were shown to be involved in the specification and patterning of the embryonic axis in vertebrates over a decade ago [1,66], no new signaling pathway has been implicated in this fundamental developmental process
Summary
A cascade of inductive events patterns the dorsoventral (DV) and anteroposterior (AP) embryonic axes through the establishment of the embryonic organizing centers (for reviews, see [1,2,3]). First discovered in amphibians and subsequently in other vertebrates, the dorsovegetal blastula organizer, named the Nieuwkoop center, initiates embryonic axis formation and later induces the dorsal gastrula, or SpemannMangold organizer (SMO), which secretes factors antagonizing Bone morphogenetic protein (BMP) signaling (reviewed by [4]). Canonical Wnt signaling is critically involved in the formation and function of both dorsal signaling centers in two sequential phases, maternal and zygotic [3,5]. At the onset of zygotic transcription, maternal b-catenin activates genes encoding transcription factors and secreted proteins that pattern embryonic axis. Maternal-effect zebrafish ichabod (ich) mutants, generated by females homozygous for a hypomorphic mutation in b-catenin-2 locus, fail to establish the Nieuwkoop center and SMO. Ich mutants lack dorsoanterior and exhibit excess ventroposterior, embryonic structures [7]
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