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Ca2ϩ signaling plays important roles during both axonal and dendritic growth. Yet whether and how Ca 2ϩ 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 2ϩ /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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Ca(2+) signaling plays a central role in activity-dependent regulation of dendritic arborization, but key molecular mechanisms downstream of calcium elevation remain poorly understood. Here we show that the C-terminal region of the Ca(2+)/calmodulin-dependent protein kinase CLICK-III (CL3)/CaMKIgamma, a membrane-anchored CaMK, was uniquely modified by two sequential lipidification steps: prenylation followed by a kinase-activity-regulated palmitoylation. These modifications were essential for CL3 membrane anchoring and targeting into detergent-resistant lipid microdomains (or rafts) in the dendrites. We found that CL3 critically contributed to BDNF-stimulated dendritic growth. Raft insertion of CL3 specifically promoted dendritogenesis of cortical neurons by acting upstream of RacGEF STEF and Rac, both present in lipid rafts. Thus, CL3 may represent a key element in the Ca(2+)-dependent and lipid-raft-delineated switch that turns on extrinsic activity-regulated dendrite formation in developing cortical neurons.

SignificanceTo extract critical information from Alzheimer’s disease (AD) postmortem brains that may otherwise be lost, we chose to screen epigenetic signatures. Epigenome analysis is a robust methodology in terms of its cell type and gene specificity, suitability for high-throughput analysis, and resistance to postmortem degradation. Analysis of the neuron-specific methylome revealed a variety of differentially methylated genes, including BRCA1. We demonstrate the pathogenic relevance of compromised genomic integrity by analyzing the neuroprotective function of BRCA1 against amyloid β (Aβ)-induced DNA double-strand breaks. Furthermore, insolubility of BRCA1 under the presence of aggregated tau suggested the reason for its dysfunction despite enhanced expression. We provide insight into the pathomechanism of AD and demonstrate the potential of screening neuron-specific methylome to reveal new pathogenic contributors.