Connexin43 controls N-cadherin transcription during collective cell migration

Abstract Connexins are the primary components of gap junctions, providing direct links between cells in many physiological processes, including cell migration and cancer metastasis. Exactly how cell migration is controlled by gap junctions remains a mystery. To shed light on this, we investigated the role of Connexin43 in collective cell migration during embryo development using the neural crest, an embryonic cell population whose migratory behavior has been likened to cancer invasion. We discovered that Connexin43 is required for contact inhibition of locomotion by directly regulating the transcription of N-cadherin. For this function, the Connexin43 carboxy tail interacts with Basic Transcription Factor 3, which mediates its translocation to the nucleus. Together, they bind to the n-cad promotor regulating n-cad transcription. Thus, we uncover an unexpected, gap junction-independent role for Connexin43 in collective migration that illustrates the possibility that connexins, in general, may be important for a wide variety of cellular processes that we are only beginning to understand. Highlights Cx43 regulates collective directional migration of neural crest cells Cx43 carboxy tail controls cell polarity via n-cad regulation Cx43 carboxy tail localises at the nucleus and that depends on BTF3 BTF3 and Cx43 carboxy tail directly interact to bind and regulate n-cad promoter activity