Journal
JOURNAL OF CELL BIOLOGY
Volume 201, Issue 5, Pages 759-776Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201212100
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Funding
- Medical Research Council
- Welcome Trust
- Fondo de Investigacion Cienntifica y Tecnologica (FONDECYT) [1120552, 24121369]
- Consejo Nacional de Investigacion Cientifica y Tecnologica (CONICYT)/Fondo de Financiamiento de Centros de Excelencia en Investigacion [15110027]
- Universidad Andres Bello (UNAB) [DI-17-12/R, DI-36-12/I]
- Company of Biologists and Boehringer Ingelheim Fonds
- Biotechnology and Biological Sciences Research Council
- Medical Research Council [MR/J000655/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10315] Funding Source: researchfish
- MRC [MR/J000655/1] Funding Source: UKRI
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One of the most important mechanisms that promotes metastasis is the stabilization of Hif-1 (hypoxia-inducible transcription factor 1). We decided to test whether Hif-1 alpha also was required for early embryonic development. We focused our attention on the development of the neural crest, a highly migratory embryonic cell population whose behavior has been likened to cancer metastasis. Inhibition of Hif-1 alpha by antisense morpholinos in Xenopus laevis or zebrafish embryos led to complete inhibition of neural crest migration. We show that Hif-1 alpha controls the expression of Twist, which in turn represses E-cadherin during epithelial to mesenchymal transition (EMT) of neural crest cells. Thus, Hif-1 alpha allows cells to initiate migration by promoting the release of cell-cell adhesions. Additionally, Hif-1 alpha controls chemotaxis toward the chemokine SDF-1 by regulating expression of its receptor Cxcr4. Our results point to Hif-1 alpha as a novel and key regulator that integrates EMT and chemotaxis during migration of neural crest cells.
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