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J. Biol. Chem., Vol. 282, Issue 1, 390-396, January 5, 2007

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The Cyclin-dependent Kinase Inhibitors p57 and p27 Regulate Neuronal Migration in the Developing Mouse Neocortex^*

Yasuhiro Itoh¹, Norihisa Masuyama, Keiko Nakayama, Keiichi I. Nakayama^¶, and Yukiko Gotoh²

From the Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan, Department of Developmental Biology, Center for Translational and Advanced Animal Research on Human Disease, Graduate School of Medicine, Tohoku University, 2-1 Seiryo, Aobaku, Sendai 980-8575, Japan, and ^¶Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan

Neuronal precursors remain in the proliferative zone of the developing mammalian neocortex until after they have undergone neuronal differentiation and cell cycle arrest. The newborn neurons then migrate away from the proliferative zone and enter the cortical plate. The molecules that coordinate migration with neuronal differentiation have been unclear. We have proposed in this study that the cdk inhibitors p57 and p27 play a role in this coordination. We have found that p57 and p27 mRNA increase upon neuronal differentiation of neocortical neuroepithelial cells. Knockdown of p57 by RNA interference resulted in a significant delay in the migration of neurons that entered the cortical plate but did not affect neuronal differentiation. Knockdown of p27 also inhibits neuronal migration in the intermediate zone as well as in the cortical plate, as reported by others. We have also found that knockdown of p27 increases p57 mRNA levels. These results suggest that both p57 and p27 play essential roles in neuronal migration and may, in concert, coordinate the timing of neuronal differentiation, migration, and possibly cell cycle arrest in neocortical development.

Received for publication, October 23, 2006

^* This work was supported by Grants-in aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan as well as SORST of the Japan Science and Technology Corporation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

¹ A research fellow of the Japan Society for the Promotion of Science.

² To whom correspondence should be addressed. Tel.: 81-3-5841-8473; Fax: 81-3-5841-8472; E-mail: ygotoh{at}iam.u-tokyo.ac.jp.

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