Zic2 regulates Draxin to promote Neural Crest cells delamination

Abstract

The Neural Crest (NC) is a population of pluripotent cells that originate in the dorsal neuroephitelium of the neural tube and travel all over the embryo to contribute to the formation of many organs. The zinc finger transcription factor Zic2 participates in several steps of neural development including neural crest formation, being initially described as crucial for neural crest cells differentiation. However, Zic2 functional experiments in different species lead to disparate conclusions and today the precise role of this transcription factor in this process is still not well defined. Here, we first show that Zic2 is expressed in premigratory but not in migrating NC cells and demonstrate that, according to previous observations, downregulation of Zic2 in chick and mice produces a decreased number of migrating NC cells in the mesenchyme concomitant with an accumulation of NC cells at the dorsal tip of the neural tube. Conversely, Zic2 gain of function produces precocious exit of NC cells from the dorsal tube, indicating that Zic2 is necessary and sufficient to induce NC cells delamination. In addition, through an unbiased genome-wide screen we have identified the secreted molecule Draxin/Neucrin, an antagonist of the Wnt canonical signaling pathway, as a Zic2 target. Functional experiments in mouse and chick confirm that Zic2 regulates Draxin/Neucrin expression, which in turn contributes to regulate the onset of NC cells delamination. Together, these observations place Zic2 and its target Neucrin/Draxin as critical players on the delamination of NC cells.