Timing dependent neuronal migration is regulated by Cdk5-meidated phosphorylation of JIP1

Abstract The evolution of the mammalian brain, particularly the cerebral cortex, is characterized by an increase in size and complexity. Proper development of the cerebral cortex involves several coordinated events such as differentiation and migration, which plays a critical role in establishing a precise six-layered architecture. Our previous study has shown that phosphorylation of JIP1 at T205 by Cdk5 affects the axonal outgrowth. However, the spatiotemporal expression patterns and functions of these three genes in different cell types during cortical development are not well understood. In this study, we interrogated single-cell RNA-sequencing (scRNA-seq) data of mouse embryonic cortex and revealed that Cdk5, Cdk5r1 (p35) and Mapk8ip1 (JIP1) are dynamically expressed in intermediate progenitors (IPs). Pseudotime analysis showed that the expression of these three genes increased simultaneously in IPs during neuronal migration and differentiation. By manipulating the expression of JIP1 and phospho-mimic JIP1 using in utero electroporation, we demonstrated that phosphorylated JIP1 at T205 influenced the temporal migration of neurons. Taken together with previous findings that phospho-JIP1 at T205 regulates axonal growth, our study reveals a mechanism by which Cdk5, p35, and JIP1 coordinate to regulate neuron specification in the developing neocortex.