Ror2 Receptor Mediates Wnt11 Ligand Signaling and Affects Convergence and Extension Movements in Zebrafish

Bai, Yan; Tan, Xungang; Zhang, Haifeng; Liu, Chengdong; Zhao, Beibei; Li, Yun; Lü, Ling; Liu, Yunzhang; Zhou, Jianfeng

doi:10.1074/jbc.m114.586099

Cited by 43 publications

(49 citation statements)

References 54 publications

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“…We next sought to determine whether in vivo perturbation of Kif26b during embryonic development results in phenotypes that are consistent with an important function for Kif26b in Wnt5a-Ror signaling during embryonic development. A previously used approach for determining if a given signaling molecule functions as part of the noncanonical Wnt pathway was to determine if mis-expression of the signaling molecule leads to a phenotype similar to that observed when Wnt5a or Rors are mis-expressed in developing Xenopus or zebrafish embryos ( Moon et al, 1993 ; Hikasa et al, 2002 ; Bai et al, 2014 ; Habas et al, 2001 ). Mis-expression of either Wnt5a or Ror2 in these embryos produces tissue morphogenesis defects, including defective convergent extension movements and a shortened or bent body axis, which are characteristic of disrupted noncanonical Wnt signaling.…”

Section: Resultsmentioning

confidence: 99%

Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates

Susman

Karuna

Kunz

et al. 2017

eLife

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Wnt5a-Ror signaling constitutes a developmental pathway crucial for embryonic tissue morphogenesis, reproduction and adult tissue regeneration, yet the molecular mechanisms by which the Wnt5a-Ror pathway mediates these processes are largely unknown. Using a proteomic screen, we identify the kinesin superfamily protein Kif26b as a downstream target of the Wnt5a-Ror pathway. Wnt5a-Ror, through a process independent of the canonical Wnt/β-catenin-dependent pathway, regulates the cellular stability of Kif26b by inducing its degradation via the ubiquitin-proteasome system. Through this mechanism, Kif26b modulates the migratory behavior of cultured mesenchymal cells in a Wnt5a-dependent manner. Genetic perturbation of Kif26b function in vivo caused embryonic axis malformations and depletion of primordial germ cells in the developing gonad, two phenotypes characteristic of disrupted Wnt5a-Ror signaling. These findings indicate that Kif26b links Wnt5a-Ror signaling to the control of morphogenetic cell and tissue behaviors in vertebrates and reveal a new role for regulated proteolysis in noncanonical Wnt5a-Ror signal transduction.

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Section: Resultsmentioning

confidence: 99%

Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates

Susman

Karuna

Kunz

et al. 2017

eLife

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“…Western blotting and Co-IP were performed mainly as described previously (Bai et al, 2014). ChIP assays were conducted using a ChIP assay kit (Millipore) according to the manufacturer's protocol.…”

Section: Co-ip Western Blotting and Chip Assaymentioning

confidence: 99%

Glutathione peroxidase 4 inhibits Wnt/β-catenin signaling and regulates dorsal organizer formation in zebrafish embryos

et al. 2017

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The Wnt/β-catenin signaling pathway plays pivotal roles in axis formation during embryogenesis and in adult tissue homeostasis. Glutathione peroxidase 4 (GPX4) is a selenoenzyme and participates in the reduction of peroxides. Its synthesis depends on the availability of the element selenium. However, the roles of GPX4 in vertebrate embryonic development and underlying mechanisms are largely unknown. Here, we show that maternal loss of zebrafish gpx4b promotes embryonic dorsal organizer formation, whereas overexpression of gpx4b inhibits the development of the dorsal organizer. Depletion of human GPX4 and zebrafish gpx4b (GPX4/ gpx4b) increases, while GPX4/gpx4b overexpression decreases, Wnt/β-catenin signaling in vivo and in vitro. Functional and epistatic studies showed that GPX4 functions at the Tcf/Lef level, independently of selenocysteine activation. Mechanistically, GPX4 interacts with Tcf/Lefs and inhibits Wnt activity by preventing the binding of Tcf/Lefs to the promoters of Wnt target genes, resulting in inhibitory action in the presence of Wnt/β-catenin signaling. Our findings unravel GPX4 as a suppressor of Wnt/β-catenin signals, suggesting a possible relationship between the Wnt/β-catenin pathway and selenium via the association of Tcf/Lef family proteins with GPX4.

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“…The importance of the WNT5A–ROR2 signaling axis in mediating osteoclastogenesis was originally established using both the global knockout and osteoclast‐specific deletion of Ror2 . While these studies are highly informative, it is difficult to disentangle the cellular effects of WNT5A using these models since other noncanonical WNTs (e.g., WNT11) signal through ROR2, and although WNT5A primarily signals through ROR2, it also interacts with RYK, ROR1, LRP‐5, and LRP‐6 . This underlines the importance of studying the cell‐of‐origin‐specific functions of WNT5A on bone homeostasis by deleting the Wnt5a gene rather than its cognate receptors.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 While these studies are highly informative, it is difficult to disentangle the cellular effects of WNT5A using these models since other noncanonical WNTs (e.g., WNT11) signal through ROR2, and although WNT5A primarily signals through ROR2, it also interacts with RYK, ROR1, LRP-5, and LRP-6. [26][27][28] This underlines the importance of studying the cellof-origin-specific functions of WNT5A on bone homeostasis by deleting the Wnt5a gene rather than its cognate receptors. In this study, we investigated the role of osteoclasts as WNT5A-secreting cells in controlling bone turnover.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Wnt5a in osteoclasts results in bone loss through decreased bone formation

Roberts

Liu

Paglia

et al. 2020

Annals of the New York Academy of Sciences

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Bone remodeling is achieved through the coupled activities of osteoclasts and osteoblasts that are controlled by many locally generated secreted factors, including WNT5A. While previous studies have demonstrated that osteoblast‐derived WNT5A promotes osteoclastogenesis, the function of osteoclast‐derived WNT5A on bone remodeling has remained unexplored. We examined the effects of osteoclast‐derived WNT5A on bone homeostasis by utilizing the Cathepsin K‐Cre (Ctsk‐Cre) mouse to conditionally delete Wnt5a in mature osteoclasts. These mice exhibited reduced trabecular and cortical bone. The low bone–mass phenotype was driven by decreased bone formation, not osteoclast‐mediated bone resorption, as osteoclast number and serum CTX marker were unchanged. Furthermore, molecular analysis of osteoclast‐ and osteoblast‐derived WNT5A identified a serine‐phosphorylated WNT5A that is unique to RANKL‐treated macrophages mimicking osteoclasts. This study suggests a new paradigm in which WNT5A has opposing effects on bone remodeling that are dependent on the cell of origin, an effect that may result from cell type–specific differential posttranslational modifications of WNT5A.

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Ror2 Receptor Mediates Wnt11 Ligand Signaling and Affects Convergence and Extension Movements in Zebrafish

Cited by 43 publications

References 54 publications

Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates

Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates

Glutathione peroxidase 4 inhibits Wnt/β-catenin signaling and regulates dorsal organizer formation in zebrafish embryos

Deletion of Wnt5a in osteoclasts results in bone loss through decreased bone formation

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