Control of cortical axon elongation by a GABA-driven Ca2+/calmodulin-dependent protein kinase cascade.
Ca(2+) signaling plays important roles during both axonal and dendritic growth. Yet whether and how Ca(2+) 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 Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK)-CaMKI cascades, CaMKK-CaMKIalpha and CaMKK-CaMKIgamma, 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-CaMKIalpha cascade critically mediated this axonogenic effect. Consistent with these findings, during early brain development, in vivo knockdown of CaMKIalpha 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-CaMKIalpha 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.
Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Natsumi
N
Ageta-Ishihara
Sayaka
S
Takemoto-Kimura
Mio
M
Nonaka
Aki
A
Adachi-Morishima
Kanzo
K
Suzuki
Satoshi
S
Kamijo
Hajime
H
Fujii
Tatsuo
T
Mano
Frank
F
Blaeser
Talal A
TA
Chatila
Hidenobu
H
Mizuno
Tomoo
T
Hirano
Yoshiaki
Y
Tagawa
Hiroyuki
H
Okuno
Haruhiko
H
Bito
D000818:Animals; D001369:Axons / Q000201:enzymology / Q000502:physiology*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism; D003712:Dendrites / Q000201:enzymology / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D015398:Signal Transduction; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D007527:Isoenzymes; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517598:Camk1 protein, mouse; C517599:Camk1 protein, rat