Hif-1α provides a Twist to neural crest migration

Barriga et al. reveal that a pathway that drives cancer cell metastasis also operates during development to promote the migration of neural crest cells.

Low oxygen levels stimulate cancer cell metastasis by stabilizing the transcription factor Hif-1α, which up-regulates genes that promote epithelial to mesenchymal transition (EMT), migration, and invasion. Barriga et al. wondered whether hypoxia and Hif-1α might also regulate similar processes during development, such as the migration of neural crest cells from the neural plate into other embryonic tissues.

Inhibiting Hif-1α expression blocked neural crest cell migration in Xenopus and zebrafish embryos. The researchers identified two key genes that were down-regulated in the absence of Hif-1α. One of these was the gene encoding the chemokine receptor Cxcr4, which binds to the chemoattractant SDF-1. Neural crest cells lacking Hif-1α couldn’t migrate toward an SDF-1 source in vitro, but chemotaxis was restored by the expression of exogenous Cxcr4.

The second key target of Hif-1α was the gene encoding Twist, a transcription factor that promotes EMT by repressing the adhesion molecule E-cadherin. E-cadherin was up-regulated in the neural crest cells of Xenopus embryos lacking Hif-1α or Twist, inhibiting their dispersal from the neuroepithelium. Because Twist and Cxcr4 are both regulated by Hif-1α in cancer cells undergoing EMT and chemotaxis, it seems that tumors can metastasize by hijacking the developmental program of neural crest cells. Senior author Roberto Mayor now wants to understand how Hif-1α, which is expressed ubiquitously, has such specific effects on the neural crest.