During embryogenesis, the epithelial-to-mesenchymal transition (EMT) is an essential morphogenetic process allowing epithelial cells to become separate migratory cells. This process is also activated when epithelial tumours develop metastases. In both cases, common gene activities such as Snail1 or Snail2 gene activation are involved. While the molecular mechanisms of Snail-induced EMT begin to be elucidated at the cellular level, little is known about the upstream regulation of these genes. To address this major challenge in developmental as well as cancer biology, the overall aim of our research is to understand how a combination of diffusible signalling molecules, multiple signal transduction pathways and their transcriptional responses are integrated and regulate Snail1/2 and other EMT-regulating factors, in normal and pathological contexts.
The neural crest is a key embryonic cell population undergoing EMT. Despite a wide interest for the early steps of development of these cells and the identification of many secreted factors and genes involved in neural crest induction, our knowledge of how these signals are integrated and how these genes are organised into an epistatic cascade is poorly documented. Our aim is to provide a comprehensive understanding of the genetic network controlling early neural crest formation during development, from its induction to EMT. We focus on the genes (transcription factors mainly) and growth factors that control Snail1 and Snail2 induction, or the genes that cooperate with Snail 1/2 to complete the EMT process. By taking advantage of the multiple ways of manipulating embryogenesis in amphibian and avian embryos, we have provided the first epistatic and functional cascade of regulations upstream of Snail1/2 in neural crest induction. Our findings in amphibian embryos have provided a novel and useful framework, now confirmed in other vertebrate species. These findings will provide critical novel clues to understand neural crest formation and control of EMT on a fundamental point of view and will also identify new molecular candidates for a precocious diagnosis of tumour progression and potential therapeutic targets.
