Abstract
The activation of distinct branches of the Wnt signaling network is essential for regulating early vertebrate development. Activation of the canonical Wnt/β-catenin pathway stimulates expression of β-catenin-Lef/Tcf regulated Wnt target genes and a regulatory network giving rise to the formation of the Spemann organizer. Non-canonical pathways, by contrast, mainly regulate cell polarization and migration, in particular convergent extension movements of the trunk mesoderm during gastrulation. By transcriptome analyses, we found caveolin1, caveolin3 and cavin1 to be regulated by Lef1 in the involuting mesoderm of Xenopus embryos at gastrula stages. We show that caveolins and caveolin dependent endocytosis are necessary for proper gastrulation, most likely by interfering with Wnt5a/Ror2 signaling. Wnt5a regulates the subcellular localization of receptor complexes, including Ror2 homodimers, Ror2/Fzd7 and Ror2/dsh heterodimers in an endocytosis dependent manner. Live-cell imaging revealed endocytosis of Ror2/caveolin1 complexes. In Xenopus explants, in the presence of Wnt5a, these receptor clusters remain stable exclusively at the basolateral side, suggesting that endocytosis of non-canonical Wnt/receptor complexes preferentially takes place at the apical membrane. In support of this blocking endocytosis with inhibitors prevents the effects of Wnt5a. Thus, target genes of Lef1 interfere with Wnt5a/Ror2 signaling to coordinate gastrulation movements.
Highlights
Different branches of the Wnt signaling network, including the Wnt/β-catenin and the β-catenin independent branches are tightly regulated to ensure proper cell differentiation and dynamics during early embryogenesis[1]
Cav1/cav[3] double knock-out mice lacking any detectable caveolae are viable[22], which suggests that mechanisms are activated in early mouse embryogenesis that can compensate for the loss of caveolae
If we first treated the embryos with low doses of genistein and subsequently added low doses of chlorpromazine, the www.nature.com/scientificreports embryos failed to gastrulate properly. These results indicate that both clathrin and caveolin dependent endocytosis pathways regulate convergent extension (CE) in a partially redundant manner
Summary
Different branches of the Wnt signaling network, including the Wnt/β-catenin and the β-catenin independent branches are tightly regulated to ensure proper cell differentiation and dynamics during early embryogenesis[1]. Activation of the canonical Wnt/β-catenin signaling pathway results in stabilization of β-catenin in the cytoplasm, which subsequently translocates into the nucleus[2] There, it binds to transcription factors of the Tcf/Lef family and regulates expression of numerous target genes, which are essential for the formation of the dorso-ventral axis[3]. Additional target genes might be important, to provide the involuting www.nature.com/scientificreports mesoderm with the competence to react to non-canonical Wnt signaling to execute gastrulation movements. These β-catenin independent Wnt signaling pathways execute their function mainly via regulation of cell shape and behavior. Cav1/cav[3] double knock-out mice lacking any detectable caveolae are viable[22], which suggests that mechanisms are activated in early mouse embryogenesis that can compensate for the loss of caveolae
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