DCC-Mediated Dab1 Phosphorylation Participates in the Multipolar-to-Bipolar Transition of Migrating Neurons

Abstract

Summary: Newborn neurons undergo inside-out migration to their final destinations during neocortical development. Reelin-induced tyrosine phosphorylation of disabled 1 (Dab1) is a critical mechanism controlling cortical neuron migration. However, the roles of Reelin-independent phosphorylation of Dab1 remain unclear. Here, we report that deleted in colorectal carcinoma (DCC) interacts with Dab1 via its P3 domain. Netrin 1, a DCC ligand, induces Dab1 phosphorylation at Y220 and Y232. Interestingly, knockdown of DCC or truncation of its P3 domain dramatically delays neuronal migration and impairs the multipolar-to-bipolar transition of migrating neurons. Notably, the migration delay and morphological transition defects are rescued by the expression of a phospho-mimetic Dab1 or a constitutively active form of Fyn proto-oncogene (Fyn), a member of the Src-family tyrosine kinases that effectively induces Dab1 phosphorylation. Collectively, these findings illustrate a DCC-Dab1 interaction that ensures proper neuronal migration during neocortical development. : Non-Reelin-induced Dab1 phosphorylation was previously identified, but not characterized. Zhang et al. find that DCC interacts with Dab1, and DCC-mediated signaling effectively induces Dab1 phosphorylation. The DCC/Dab1 signaling complex is essential for neuronal migration, especially during the multipolar-to-bipolar transition. Keywords: Dab1, DCC, Fyn, morphological transition, netrin 1, neocortex development, neuronal migration, Reelin, tyrosine phosphorylation