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

Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA.
Developmental Biology (Impact Factor: 3.55). 06/2012; 368(2):335-44. DOI: 10.1016/j.ydbio.2012.05.036
Source: PubMed


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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Available from: Hélène Cousin
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    • "In addition, we previously showed that ADAM13 and 19 activity was essential in the leading CNC but that morphant cells could follow wild-type cells in grafts (Cousin et al., 2012). Similarly, in chickens, ADAM13 is expressed more abundantly in the leading cells than in the followers (McLennan et al., 2012). "
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    ABSTRACT: 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 multiple genes' expression via its cytoplasmic domain. The latter activity is regulated by γ-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. While the nuclear function of ADAM13 is evolutionarily conserved, it is unclear if 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, γ-secretase cleavage or nuclear translocation of its cytoplasmic domain. Significantly, migration of the CNC can be restored in the absence of Plk phosphorylation by expression of Calpain-8a, pointing to an impaired nuclear activity of ADAM13.
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    ABSTRACT: Neural crest cells are highly migratory cells that give rise to many derivatives including peripheral ganglia, craniofacial structures and melanocytes. Neural crest cells migrate along defined pathways to their target sites, interacting with each other and their environment as they migrate. Cell adhesion molecules are critical during this process. In this review we discuss the expression and function of cell adhesion molecules during the process of neural crest migration, in particular cadherins, integrins, members of the immunoglobulin superfamily of cell adhesion molecules, and the proteolytic enzymes that cleave these cell adhesion molecules. The expression and function of these cell adhesion molecules and proteases are compared across neural crest emigrating from different axial levels, and across different species of vertebrates.
    Preview · Article · Oct 2012 · Developmental Biology
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    ABSTRACT: Abstract The neural crest (NC) is a population of migratory stem/progenitor cells that is found in early vertebrate embryos. NC cells are induced during gastrulation, and later migrate to multiple destinations and contribute to many types of cells and tissues, such as craniofacial structures, cardiac tissues, pigment cells and the peripheral nervous system. Recently, accumulating evidence suggests that many extracellular metalloproteinases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin motifs (ADAMTSs), play important roles in various stages of NC development. Interference with metalloproteinase functions often causes defects in craniofacial structures, as well as in other cells and tissues that are contributed by NC cells, in humans and other vertebrates. In this review, we summarize the current state of the field concerning the roles of these three families of metalloproteinases in NC development and related tissue morphogenesis, with a special emphasis on craniofacial morphogenesis.
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