XB-ART-47147J Cell Biol. May 27, 2013; 201 (5): 759-76.
The hypoxia factor Hif-1α controls neural crest chemotaxis and epithelial to mesenchymal transition.
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-1α 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-1α by antisense morpholinos in Xenopus laevis or zebrafish embryos led to complete inhibition of neural crest migration. We show that Hif-1α controls the expression of Twist, which in turn represses E-cadherin during epithelial to mesenchymal transition (EMT) of neural crest cells. Thus, Hif-1α allows cells to initiate migration by promoting the release of cell-cell adhesions. Additionally, Hif-1α controls chemotaxis toward the chemokine SDF-1 by regulating expression of its receptor Cxcr4. Our results point to Hif-1α as a novel and key regulator that integrates EMT and chemotaxis during migration of neural crest cells.
PubMed ID: 23712262
PMC ID: PMC3664719
Article link: J Cell Biol.
Grant support: Biotechnology and Biological Sciences Research Council , Medical Research Council , Wellcome Trust
Genes referenced: cad cald1 cdh1 ctrl cxcl12 cxcr4 itk snai1 snai2 sox10 sst twist1
Article Images: [+] show captions
|Figure 1. Hif-1α is required for neural crest migration. (A–Q) Xenopus (A–H) and zebrafish (I–Q) embryos were injected with antisense MOs as indicated in the figure, and the expression of the neural crest markers Snail2 (A–H) or crestin (I–M) was analyzed. Asterisks show the injected side. (A–D) No effect of ATGMOhif-1α on neural crest induction. (E–H) Strong effect of ATGMOhif-1α on neural crest migration. (I–J′) Dorsal (I and J) or lateral (I′ and J′) view of zebrafish embryos. (J) Note that in ATGMOhif-1α–injected embryos, neural crests are present around to the dorsal midline. (L) Percentage of embryos with the described phenotype. (M) The number of neural crest streams was counted by analyzing the expression of crestin for each treatment. (K, K′, and M) Note that the number of streams is reduced with the ATGMOhif-1α but rescued by the coinjection of Hif-1α mRNA. (N–Q) Analysis of cartilage development in zebrafish embryos. The bars in D, H, L, M, and Q histograms represent the standard deviations of three independent experiments, with ∼40 embryos used in each case. som, somite.|
|Figure 5. Hif-1α gain of function induces cell dispersion and inhibits chemotaxis. Chemotaxis was analyzed as described in Fig. 4 for each treatment as indicated at the top of the figure. (A–E) Time 0. (F–J) 3 h after culture. (K–O) Tracks of migrating cells. (P–T) Angles of migration for individual cells. (U) Cell velocity. (V) Persistence. (W) Chemotaxis index. Each experiment was performed at least three times, and ∼60 cells were analyzed for each treatment. ***, P < 0.005. Errors bars represent standard deviation.|
|Figure 9. Model of Hif-1 controlling neural crest migration. Neural crest, shown as blue cells, delaminates from the neural tube (NT). Prospective neural crest expresses E-cadherin (E-cad; red), just before EMT Hif-1α activates Twist, which in turn represses E-cadherin expression, allowing neural crest EMT. In addition, Hif-1α activates Cxcr4, which is required for chemotaxis toward SDF-1.|