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ADAM13 induces cranial neural crest by cleaving class B Ephrins and regulating Wnt signaling.

ABSTRACT: The cranial neural crest (CNC) consists of multipotent embryonic cells that contribute to craniofacial structures and other cells and tissues of the vertebrate head. During embryogenesis, CNC is induced at the neural plate boundary through the interplay of several major signaling pathways. Here, we report that the metalloproteinase activity of ADAM13 is required for early induction of CNC in Xenopus. In both cultured cells and X. tropicalis embryos, membrane-bound Ephrins (Efns) B1 and B2 were identified as substrates for ADAM13. ADAM13 upregulates canonical Wnt signaling and early expression of the transcription factor snail2, whereas EfnB1 inhibits the canonical Wnt pathway and snail2 expression. We propose that by cleaving class B Efns, ADAM13 promotes canonical Wnt signaling and early CNC induction.

SUBMITTER: Wei S

PROVIDER: S-EPMC2951023 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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ADAM13 induces cranial neural crest by cleaving class B Ephrins and regulating Wnt signaling.

Wei Shuo S Xu Guofeng G Bridges Lance C LC Williams Phoebe P White Judith M JM DeSimone Douglas W DW

Developmental cell 20100801 2

The cranial neural crest (CNC) consists of multipotent embryonic cells that contribute to craniofacial structures and other cells and tissues of the vertebrate head. During embryogenesis, CNC is induced at the neural plate boundary through the interplay of several major signaling pathways. Here, we report that the metalloproteinase activity of ADAM13 is required for early induction of CNC in Xenopus. In both cultured cells and X. tropicalis embryos, membrane-bound Ephrins (Efns) B1 and B2 were i ...[more]

PMID: 20708595

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ADAM13 knockdown in Xenopus laevis cranial neural crest

Project description:ADAMs are transmembrane metalloproteases that control cell behavior by cleaving both cell adhesion and signaling molecules. The cytoplasmic domain of ADAMs can regulate the proteolytic activity by controlling the subcellular localization and/or the activation of the protease domain. Here we show that the cytoplasmic domain of ADAM13 is cleaved and translocates into the nucleus. Preventing this translocation renders the protein incapable of promoting cranial neural crest (CNC) cell migration in vivo, without affecting its proteolytic activity. In addition, the cytoplasmic domain of ADAM13 regulates the expression of multiple genes in the CNC. This study shows that the cytoplasmic domain of ADAM metalloproteases can perform essential functions in the nucleus of cells and may contribute substantially to the overall function of the protein. Total RNA from cranial neural crest explants dissected from Xenopus laevis embryos at stage 15 to 17. Embryos were injected with either control morpholino (CMO), morpholino to ADAM13 (MO13) or MO13 and a fusion between GFP- and the cytoplasmic domain of ADAM13 (GFP-C13). Triplicate microarray correspond to independent experiments labeled DA4, DA5 and DA2. For each sample 1 is CMO, sample 2 is MO13 and sample 3 is MO13+C13. Embryos were injected with 10 ng of morpholino and 0.5 ng of GFP-C13 mRNA. Supplementary files: [1] matrix2_sig-genes.txt CNC array: Genes significantly affected by the loss of ADAM13 p<0.01. Normalized probe set generated by GC-RMA. [2] matrix3_sig-genes.txt CNC array: Genes significantly affected by the loss of ADAM13 and the addition of GFP-C13 p<0.01. Normalized probe set generated by GC-RMA.

2011-02-22 | E-GEOD-21517 | biostudies-arrayexpress

ADAM13 knockdown in Xenopus laevis cranial neural crest

2011-02-22 | GSE21517 | GEO

GSK3 and Polo-like kinase regulate ADAM13 function during cranial neural crest cell migration.

Project description:ADAMs are cell surface metalloproteases that control multiple biological processes by cleaving signaling and adhesion molecules. ADAM13 controls cranial neural crest (CNC) cell migration both by cleaving cadherin-11 to release a promigratory extracellular fragment and by controlling expression of multiple genes via its cytoplasmic domain. The latter activity is regulated by ?-secretase cleavage and the translocation of the cytoplasmic domain into the nucleus. One of the genes regulated by ADAM13, the protease calpain8, is essential for CNC migration. Although the nuclear function of ADAM13 is evolutionarily conserved, it is unclear whether the transcriptional regulation is also performed by other ADAMs and how this process may be regulated. We show that ADAM13 function to promote CNC migration is regulated by two phosphorylation events involving GSK3 and Polo-like kinase (Plk). We further show that inhibition of either kinase blocks CNC migration and that the respective phosphomimetic forms of ADAM13 can rescue these inhibitions. However, these phosphorylations are not required for ADAM13 proteolysis of its substrates, ?-secretase cleavage, or nuclear translocation of its cytoplasmic domain. Of significance, migration of the CNC can be restored in the absence of Plk phosphorylation by expression of calpain-8a, pointing to impaired nuclear activity of ADAM13.

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Xenopus ADAM19 regulates Wnt signaling and neural crest specification by stabilizing ADAM13.

Project description:During vertebrate gastrulation, canonical Wnt signaling induces the formation of neural plate border (NPB). Wnt is also thought to be required for the subsequent specification of neural crest (NC) lineage at the NPB, but the direct evidence is lacking. We found previously that the disintegrin metalloproteinase ADAM13 is required for Wnt activation and NC induction in Xenopus Here, we report that knockdown of ADAM13 or its close paralog ADAM19 severely downregulates Wnt activity at the NPB, inhibiting NC specification without affecting earlier NPB formation. Surprisingly, ADAM19 functions nonproteolytically in NC specification by interacting with ADAM13 and inhibiting its proteasomal degradation. Ectopic expression of stabilized ADAM13 mutants that function independently of ADAM19 can induce the NC marker/specifier snail2 in the future epidermis via Wnt signaling. These results unveil the essential roles of a novel protease-protease interaction in regulating a distinct wave of Wnt signaling, which directly specifies the NC lineage.

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Cranial Neural Crest Explants.

Project description:The cranial neural crest (CNC) explant assay was originally designed to assess the basic requirements for CNC migration in vitro. This protocol describes the key parameters of CNC explants in Xenopus laevis, with a focus on how to extirpate CNC cells and assay their migration in vitro. The protocol can be adapted according to the needs of the experimenter, some examples of which are discussed here.

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Cranial Neural Crest Transplants.

Project description:The transplantation of cranial neural crest (CNC) expressing green fluorescent protein (GFP) in Xenopus laevis has allowed researchers not only to assess CNC migration in vivo but also to address many other experimental questions. Coupled with loss- or gain-of-function experiments, this technique can be used to characterize the function of specific genes during CNC migration and differentiation. Although targeted injection can also be used to assess gene function during CNC migration, CNC transplantation allows one to answer specific questions, such as whether a gene's function is tissue autonomous, cell autonomous, or exerted in the tissues surrounding the CNC. Here we describe a protocol for performing simple CNC grafts.

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ADAM13 function is required in the 3 dimensional context of the embryo during cranial neural crest cell migration in Xenopus laevis.

Project description:The cranial neural crest (CNC) is a population of cells that arises from the lateral part of the developing brain, migrates ventrally and coordinates the entire craniofacial development of vertebrates. Many molecules are involved in CNC migration including the transmembrane metalloproteases ADAM13 and 19. We have previously shown that these ADAMs cleave a number of extracellular proteins and modify the transcription of a number of genes, and that both of these activities are important for cell migration. Here we show that the knock down of ADAM13 inhibits CNC migration in vivo but not in vitro, indicating that ADAM13 function is required in the 3-dimentional context of the embryo. We further show that the migration of CNC that do not express ADAM13 and ADAM19 can be rescued in vivo by co-grafting wild type CNC. Furthermore, the migration of CNC lacking ADAM13 can be rescued by mechanically separating the CNC from the surrounding ectoderm and mesoderm. Finally, we show that ADAM13 function is autonomous to CNC tissue, as the migration of morphant CNC can only be rescued by ADAM13 expression in the CNC and not the surrounding tissues. Together our results suggest that ADAM13 changes CNC interaction with the extracellular environment and that this change is necessary for their migration in vivo.

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Translocation of the cytoplasmic domain of ADAM13 to the nucleus is essential for Calpain8-a expression and cranial neural crest cell migration.

| S-EPMC3074609 | biostudies-literature

The Wnt Co-Receptor Lrp5 Is Required for Cranial Neural Crest Cell Migration in Zebrafish.

Project description:During vertebrate neurulation, cranial neural crest cells (CNCCs) undergo epithelial to mesenchymal transition (EMT), delaminate from the neural plate border, and migrate as separate streams into different cranial regions. There, they differentiate into distinct parts of the craniofacial skeleton. Canonical Wnt signaling has been shown to be essential for this process at different levels but the involved receptors remained unclear. Here we show that the frizzled co-receptor low-density-lipoprotein (LDL) receptor-related protein 5 (Lrp5) plays a crucial role in CNCC migration and morphogenesis of the cranial skeleton. Early during induction and migration of CNCCs, lrp5 is expressed ubiquitously but later gets restricted to CNCC derivatives in the ventral head region besides different regions in the CNS. A knock-down of lrp5 does not interfere with induction of CNCCs but leads to reduced proliferation of premigratory CNCCs. In addition, cell migration is disrupted as CNCCs are found in clusters at ectopic positions in the dorsomedial neuroepithelium after lrp5 knock-down and transient CRISPR/Cas9 gene editing. These migratory defects consequently result in malformations of the craniofacial skeleton. To date, Lrp5 has mainly been associated with bone homeostasis in mammals. Here we show that in zebrafish, lrp5 also controls cell migration during early morphogenetic processes and contributes to shaping the craniofacial skeleton.

| S-EPMC4486457 | biostudies-literature

SMAD4-mediated WNT signaling controls the fate of cranial neural crest cells during tooth morphogenesis.

Project description:TGF?/BMP signaling regulates the fate of multipotential cranial neural crest (CNC) cells during tooth and jawbone formation as these cells differentiate into odontoblasts and osteoblasts, respectively. The functional significance of SMAD4, the common mediator of TGF?/BMP signaling, in regulating the fate of CNC cells remains unclear. In this study, we investigated the mechanism of SMAD4 in regulating the fate of CNC-derived dental mesenchymal cells through tissue-specific inactivation of Smad4. Ablation of Smad4 results in defects in odontoblast differentiation and dentin formation. Moreover, ectopic bone-like structures replaced normal dentin in the teeth of Osr2-IresCre;Smad4(fl/fl) mice. Despite the lack of dentin, enamel formation appeared unaffected in Osr2-IresCre;Smad4(fl/fl) mice, challenging the paradigm that the initiation of enamel development depends on normal dentin formation. At the molecular level, loss of Smad4 results in downregulation of the WNT pathway inhibitors Dkk1 and Sfrp1 and in the upregulation of canonical WNT signaling, including increased ?-catenin activity. More importantly, inhibition of the upregulated canonical WNT pathway in Osr2-IresCre;Smad4(fl/fl) dental mesenchyme in vitro partially rescued the CNC cell fate change. Taken together, our study demonstrates that SMAD4 plays a crucial role in regulating the interplay between TGF?/BMP and WNT signaling to ensure the proper CNC cell fate decision during organogenesis.

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