Cdk5 regulates differentiation of oligodendrocyte precursor cells through the direct phosphorylation of paxillin

Abstract

Oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes (OLs) in order to form myelin, which is required for the rapid propagation of action potentials in the vertebrate nervous system. In spite of the considerable clinical importance of myelination, little is known about the basic molecular mechanisms underlying OL differentiation and myelination. Here, we show that cyclin-dependent kinase (Cdk) 5 is activated following the induction of differentiation, and that the Cdk5 inhibitor roscovitine inhibits OL differentiation. The complexity of the OL processes is also diminished after knocking down endogenous Cdk5 using RNAi. We also show that the focal adhesion protein paxillin is directly phosphorylated at Ser244 by Cdk5. Transfection of a paxillin construct harboring a Ser244 to Ala mutation dramatically inhibits its morphological effects. Importantly, phosphorylation of paxillin at Ser244 reduces its interaction with focal adhesion kinase (FAK). Taken together, these results suggest that phosphorylation of paxillin by Cdk5 is a key mechanism in OL differentiation and may ultimately regulate myelination.

p39, the Primary Activator for Cyclin-dependent Kinase 5 (Cdk5) in Oligodendroglia, Is Essential for Oligodendroglia Differentiation and Myelin Repair

“…3D). Thus, the developmentally programmed up-regulation of p39 mRNA leads to increased production of p39 protein, which underlies the increase of Cdk5 activity during OL and myelin development reported by previous studies (11,12).…”

“…Previous studies have established the essential role of Cdk5 in OPC development (12). We next asked whether p39-mediated activation of Cdk5 advances OPC differentiation.…”

“…p39, but Not p35, Is Up-regulated during OL and Myelin Development-During OL differentiation, Cdk5 activity is markedly up-regulated (11,12). To explore which activator is responsible for the enhanced Cdk5 activity, we analyzed the expression levels of Cdk5 and its activators during OL differen- Ϫ/Ϫ brain, primary cultured rat neurons (N), astrocytes (A), OLs, and CG4 cells were subjected to immunoblot analysis of p39, p35, Cdk5, and eIF5␣.…”

“…Earlier studies demonstrated essential functions of Cdk5 in neuronal migration, neural network formation, and synaptic plasticity in mammalian brains (5). Besides the traditional view of neuronal centric roles of Cdk5, emerging evidence suggests that Cdk5 also governs the development of oligodendroglia progenitor cells (OPCs) (11)(12)(13). Similar to brain neurons, OPCs migrate to distant brain areas and become mature OLs to myelinate neuronal axons (14).…”

“…However, unlike neuronal development in the embryonic brains, the most vigorous OPC development occurs postnatally (14). Loss of Cdk5 function affects OPC migration and differentiation in culture and results in CNS hypomyelination (12,13,15,16). However, molecular mechanisms that regulate Cdk5 function in neurons and OLs remain elusive.…”