Requirement of CRMP2 Phosphorylation in Neuronal Migration of Developing Mouse Cerebral Cortex and Hippocampus and Redundant Roles of CRMP1 and CRMP4

Abstract

The mammalian cerebral cortex is characterized by a 6-layer structure, and proper neuronal migration is critical for its formation. Cyclin-dependent kinase 5 (Cdk5) has been shown to be a critical kinase for neuronal migration. Several Cdk5 substrates have been suggested to be involved in ordered neuronal migration. However, in vivo loss-of-function studies on the function of Cdk5 phosphorylation substrates in neuronal migration in the developing cerebral cortex have not been reported. In this study, we demonstrated that Cdk5-mediated phosphorylation of collapsing mediator protein (CRMP) 2 is critical for neuronal migration in the developing cerebral cortex with redundant functions of CRMP1 and CRMP4. The cerebral cortices of triple-mutant CRMP1 knock-out (KO); CRMP2 knock-in (KI)/KI; and CRMP4 KO mice showed disturbed positioning of layers II–V neurons in the cerebral cortex. Further experiments using bromodeoxyuridine birthdate-labeling and in utero electroporation implicated radial migration defects in cortical neurons. Ectopic neurons were detected around the CA1 region and dentate gyrus in CRMP1 KO; CRMP2 KI/KI; and CRMP4 KO mice. These results suggest the importance of CRMP2 phosphorylation by Cdk5 and redundancy of CRMP1 and CRMP4 in proper neuronal migration in the developing cerebral cortex and hippocampus.

DPYSL2/CRMP2isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

“…It is most well-known as a microtubule-stabilizing protein that functions by forming tetramers with itself or other CRMPs that stabilize assembled microtubules and traffic tubulin dimers to their plus end 4 . Consequently, CRMP2 is a mitigator of diverse cytoskeletal-related functions including mitosis, cell migration 5; 6 , endocytosis, mitochondrial morphology and motility 7 , kinesin and dynein-facilitated molecular transport, cell polarity, and dendritic and axonal elongation 2; 8; 9 . Additionally, CRMP2 acts as a modulator of calcium homeostasis and neurotransmitter release by both regulating the trafficking of calcium channel subunits and binding to NMDAR receptors to inhibit their activity 2; 10; 11 .…”