Journal
JOURNAL OF NEUROSCIENCE
Volume 29, Issue 43, Pages 13720-13729Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3018-09.2009
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Ministry of Health, Labour and Welfare of Japan
- Century Center of Excellence (COE)
- Global COE Programmes
- National Institutes of Health
- Astellas Foundation for Research on Metabolic Disorders
- Naito Foundation
- Cell Science Research Foundation
- Takeda Foundation
- Toray Science Foundation
- Japan Society for the Promotion of Science
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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 alpha and CaMKK-CaMKI gamma, critically coordinate axonal and dendritic morphogenesis of cortical neurons, respectively. The axon-specific morphological phenotype required a diffuse cytoplasmic localization and a strikingly alpha-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 alpha cascade critically mediated this axonogenic effect. Consistent with these findings, during early brain development, in vivo knockdown of CaMKI alpha 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 alpha 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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