Asymmetric localisation of DLC1 defines neural crest polarity for directional migration

Abstract

Coordinated regulation of directional neural crest delamination is essential for the subsequent migration and differentiation into different derivatives. Among the molecules that regulate neural crest development, SoxE family transcription factors, in addition to acting as neural crest specifiers, together with Rho GTPases play key roles in directing neural crest migratory behavior but how these two classes of factors are functionally linked is unclear. Here, we show that RhoA is highly active and enriched at the rear part of the cell body while it is also dynamically localized at the protrusive front in the direction of migration. This polarized RhoA activity determines the head-tail (or front-rear) polarity of the cell for directed migration and is regulated by an asymmetric expression of Rho GAP isoform, Dlc1α. Both dominant-negative inhibition and overexpression of Dlc1α results in reduced neural crest delamination due to altered front-back polarized RhoA activity that affects directional migratory behavior. Furthermore, mass spectrometry analysis identify Nedd9 to partner with Dlc1α and is required for its polarized expression. Dlc1 and Nedd9 are subjected to the transcriptional regulation of SoxE family members. Together, these data reveal a novel SoxE-Dlc1/Nedd9-RhoA regulatory axis to govern directional delamination of neural crest cells.