Connexins and gap junctions in cell migration : CX43 regulates N-cadherin expression during collective migration

Collective migration is a fundamental process in tissue homeostasis, cancer metastasis and embryo development, which involves coordination and cooperation between migrating cells. However, the mechanisms that govern cell cooperation during migration remain elusive. Here, I investigate the role of gap junctions and their protein components, connexins, in neural crest, a collectively migrating embryonic cell population. I demonstrate that two connexins are expressed in Xenopus laevis neural crest and are required for its migration in vivo. Furthermore, this requirement is specific for collective directional migration, but not for individual motility in vitro. Exploring the effect on collective movement, I found that Connexin43 is essential for cell polarity and cell-cell adhesion. Furthermore, Cx43 inhibition leads to a decrease in N-cadherin protein levels due to a decrease on mRNA levels. I show that Cx43 controls N-cadherin transcription via its carboxy-terminal tail, which needs to be localised at the nucleus in order to exert its function. Additionally, I show that functional gap junction channels are formed in Xenopus laevis neural crest and that inhibition of these channels perturbs neural crest migration. However, the channel activity does not affect N-cadherin expression. It is apparent that in Xenopus neural crest, connexins play a dual role to regulate its migration: the channel function and the Cx43 tail channelindependent signalling. This study provides evidence for the first time that a typical gap junction protein, Connexin43, is promoting collective cell migration by employing a novel mechanism of transcriptional regulation of the adhesion molecule N-cadherin via its carboxy terminal fragment.