CRMP2 and its phosphorylation prevent axonal misrouting of the corticospinal tract

During the development of the central nervous system (CNS), the formation of neural circuits such as the corticospinal tract (CST) is crucial to control voluntary movement and is regulated by axonal guidance mechanisms. In this study, we examined the role of CRMP2 (Collapsin response mediator protein 2) in the formation of CST. CRMP2, which binds to actin and microtubules to control the cytoskeleton, is a phosphoprotein whose activity depends on its phosphorylated state. To inhibit Cyclin-dependent kinase 5 (Cdk5) phosphorylation, CRMP2 knock-in (crmp2^ki/ki) mice were generated in which the serine residue at position 522 was replaced with alanine. Our results showed that both CRMP2 knock-out (crmp2^-/-) and crmp2^ki/ki mice exhibited higher percentages of CST axons that crossed the midline erroneously than wild-type (WT) mice. However, in mice lacking CRMP1, which is highly homologous to CRMP2, few axons crossed the midline, similar to WT mice. Additionally, crmp2^-/- and crmp2^ki/ki mice showed decreased proportions of independent forelimb movements. These findings emphasize that CRMP2 and its phosphorylation are necessary for proper CST formation in the mouse CNS.