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The Journal of Neuroscience, August 13, 2008, 28(33):8326-8337; doi:10.1523/JNEUROSCI.1482-08.2008

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Cellular/Molecular
Cdk5 Phosphorylation of WAVE2 Regulates Oligodendrocyte Precursor Cell Migration through Nonreceptor Tyrosine Kinase Fyn

Yuki Miyamoto,¹ Junji Yamauchi,^1,2 and Akito Tanoue¹

¹Department of Pharmacology, National Research Institute for Child Health and Development, Okura, Setagaya, Tokyo 157-8535, Japan, and ²Department of Biological Sciences, Tokyo Institute of Technology, Midori, Nagatsuta, Yokohama 226-8501, Japan

Correspondence should be addressed to Junji Yamauchi, Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan. Email: jyamauchi{at}nch.go.jp

Myelin formation of the CNS is a complex and dynamic process. Before the onset of myelination, oligodendrocytes (OLs), the myelin-forming glia of the CNS, proliferate and migrate along axons. Little is known about the molecular mechanisms underlying the early myelination processes. Here, we show that platelet-derived growth factor (PDGF), the crucial physiological ligand in early OL development, controls the migration of oligodendrocyte precursor cells (OPCs) through cyclin-dependent kinase 5 (Cdk5). PDGF stimulates Cdk5 activity in a time-dependent manner, whereas suppression of Cdk5 by the specific inhibitor roscovitine or by the retrovirus encoding short-hairpin RNA for Cdk5 impairs PDGF-dependent OPC migration. The activation of Cdk5 by PDGF is mediated by the phosphorylation of the nonreceptor tyrosine kinase, Fyn, whose inhibition reduces PDGF-dependent OPC migration. Furthermore, Cdk5 regulates PDGF-dependent OPC migration through the direct phosphorylation of WASP (Wiskott–Aldrich syndrome protein)-family verprolin-homologous protein 2 (WAVE2). Cdk5 phosphorylates WAVE2 at Ser-137 in vitro. Infection of the WAVE2 construct harboring the Ser-137-to-Ala reduces PDGF-dependent migration. Together, PDGF regulates OPC migration through an as-yet-unidentified signaling cascade coupling Fyn kinase to Cdk5 phosphorylation of WAVE2. These results provide new insights into both the role of Cdk5 in glial cells and the molecular mechanisms controlling the early developmental stage of OLs.

Key words: oligodendrocytes; migration; phosphorylation; Cdk5; WAVE2; CNS

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Received April 7, 2008; revised June 20, 2008; accepted July 11, 2008.

Correspondence should be addressed to Junji Yamauchi, Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan. Email: jyamauchi{at}nch.go.jp

Related articles in J. Neurosci.:

Intracellular Signaling Mechanisms Directing Oligodendrocyte Precursor Cell Migration

Sathyanath Rajasekharan
J. Neurosci. 2008 28: 13365-13367. [Full Text]  

This article has been cited by other articles:

				S. Rajasekharan Intracellular Signaling Mechanisms Directing Oligodendrocyte Precursor Cell Migration J. Neurosci., December 10, 2008; 28(50): 13365 - 13367. [Full Text] [PDF]

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