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The Journal of Neuroscience, October 28, 2009, 29(43):13720-13729; doi:10.1523/JNEUROSCI.3018-09.2009

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Cellular/Molecular
Control of Cortical Axon Elongation by a GABA-Driven Ca²⁺/Calmodulin-Dependent Protein Kinase Cascade

Natsumi Ageta-Ishihara,¹ Sayaka Takemoto-Kimura,¹ Mio Nonaka,¹ Aki Adachi-Morishima,¹ Kanzo Suzuki,¹ Satoshi Kamijo,¹ Hajime Fujii,¹ Tatsuo Mano,¹ Frank Blaeser,² Talal A. Chatila,³ Hidenobu Mizuno,^4,5 Tomoo Hirano,^4,5 Yoshiaki Tagawa,^4,5 Hiroyuki Okuno,^1,5 and Haruhiko Bito^1,5

¹Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan, ²Institute of Transfusion Medicine, University Hospital Leipzig, 04129 Leipzig, Germany, ³Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095-1752, ⁴Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 606-8502, Japan, and ⁵Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan

Correspondence should be addressed to Haruhiko Bito, Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Email: hbito{at}m.u-tokyo.ac.jp

Ca²⁺ signaling plays important roles during both axonal and dendritic growth. Yet whether and how Ca²⁺ rises may trigger and contribute to the development of long-range cortical connections remains mostly unknown. Here, we demonstrate that two separate limbs of the Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK)–CaMKI cascades, CaMKK–CaMKI and CaMKK–CaMKI, critically coordinate axonal and dendritic morphogenesis of cortical neurons, respectively. The axon-specific morphological phenotype required a diffuse cytoplasmic localization and a strikingly -isoform-specific kinase activity of CaMKI. Unexpectedly, treatment with muscimol, a GABA_A receptor agonist, selectively stimulated elongation of axons but not of dendrites, and the CaMKK–CaMKI cascade critically mediated this axonogenic effect. Consistent with these findings, during early brain development, in vivo knockdown of CaMKI significantly impaired the terminal axonal extension and thereby perturbed the refinement of the interhemispheric callosal projections into the contralateral cortices. Our findings thus indicate a novel role for the GABA-driven CaMKK–CaMKI cascade as a mechanism critical for accurate cortical axon pathfinding, an essential process that may contribute to fine-tuning the formation of interhemispheric connectivity during the perinatal development of the CNS.

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Received June 25, 2009; revised Aug. 18, 2009; accepted Sept. 29, 2009.

Correspondence should be addressed to Haruhiko Bito, Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Email: hbito{at}m.u-tokyo.ac.jp

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