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Published online 21 April 2003. doi:10.1083/jcb.200210149
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© The Rockefeller University Press, 0021-9525/2003/4/381 $5.00
The Journal of Cell Biology, Volume 161, Number 2, 381-391

Article

Control of axon elongation via an SDF-1{alpha}/Rho/mDia pathway in cultured cerebellar granule neurons



Yoshiki Arakawa1,2, Haruhiko Bito1,3,4, Tomoyuki Furuyashiki1, Takahiro Tsuji1, Sayaka Takemoto-Kimura1, Kazuhiro Kimura1, Kazuhiko Nozaki2, Nobuo Hashimoto2 and Shuh Narumiya1

1 Department of Pharmacology, Kyoto University Faculty of Medicine
2 Department of Neurosurgery, Kyoto University Faculty of Medicine
3 PRESTO-Japan Science and Technology Corporation, Sakyo-ku, Kyoto 606-8315, Japan
4 Department of Neurochemistry, University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo 113-0033, Japan

Address correspondence to Shuh Narumiya, Dept. of Pharmacology, Kyoto University Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606-8315, Japan. Tel.: 81-75-753-4392. Fax: 81-75-753-4693. E-mail: snaru{at}mfour.med.kyoto-u.ac.jp

Rho–GTPase has been implicated in axon outgrowth. However, not all of the critical steps controlled by Rho have been well characterized. Using cultured cerebellar granule neurons, we show here that stromal cell–derived factor (SDF)-1{alpha}, a neural chemokine, is a physiological ligand that can turn on two distinct Rho-dependent pathways with opposite consequences. A low concentration of the ligand stimulated a Rho-dependent pathway that mediated facilitation of axon elongation. In contrast, Rho/ROCK activation achieved by a higher concentration of SDF-1{alpha} caused repression of axon formation and induced no more increase in axon length. However, even at this higher concentration a Rho-dependent axon elongating activity could be recovered upon removal of ROCK activity using Y-27632. SDF-1{alpha}–induced axon elongating activity under ROCK inhibition was replicated by the dominant-active form of the mammalian homologue of the Drosophila gene Diaphanous (mDia)1 and counteracted by its dominant-negative form. Furthermore, RNAi knockdown of mDia1 abolished SDF-1{alpha}–induced axon elongation. Together, our results support a critical role for an SDF-1{alpha}/Rho/mDia1 pathway in mediating axon elongation.

Key Words: mDia; Rho; axon elongation; cerebellar granule neuron; SDF-1{alpha}

The online version of this article includes supplemental material.

* Abbreviations used in this paper: CRIB, Cdc42/Rac interactive binding; CNS, central nervous system; DA, dominant-active; DN, dominant-negative; EGFP, enhanced GFP; EGL, external granule cell layer; IGL, internal granule cell layer; mDia, mammalian homologue of the Drosophila gene Diaphanous; P, postnatal day; PAK, p21-associated kinase; RBD, Rho-binding domain; RNAi, RNA interference; siRNA, short interfering double stranded RNA oligomer; SDF, stromal cell–derived factor.


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