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Emilie Pacary, Olivier Nicole et al. dans Mol Psychiatry

CaMKIIβ: un régulateur crucial de la migration neuronale lors du développement du cortex cérébral

Le 2 mai 2018

A novel role for CAMKIIβ in the regulation of cortical neuron migration: implications for neurodevelopmental disorders. Olivier Nicole, Donald M. Bell, Thierry Leste-Lasserre, Hélène Doat, François Guillemot & Emilie Pacary. Molecular Psychiatry (2018) doi:10.1038/s41380-018-0046-0

Olivier Nicole, CR CNRS in the team “Dynamics of neuronal and vascular networks underlying memory processing” (Team leader: Dr Bruno Bontempi). CNRS, UMR5293, Institut des Maladies Neurodégénératives. Emilie Pacary, CR INSERM in the team “Neurogenesis and pathophysiology” (Team leader: Dr Nora Abrous). INSERM U1215, Neurocentre Magendie.

 


 A series of recent studies indicate that CaMKII dysfunction is associated with a wide variety of psychiatric and neurodevelopmental diseases,
including depression, schizophrenia, epilepsy and various forms of mental retardation [see review by Robison, Trends Neurosci 37(11):653-62 2014]. CaMKII is a major protein in the brain, accounting for 1-2% of total brain proteins. Because of this abundance and as main player in Ca2+ signaling, CaMKII represents a critical link between the external environment and cellular responses in neurons. Brain CaMKII predominantly consists of the α and β isoforms, which form heteromeric or homomeric complexes. While the α isoform has been studied extensively, probably because of its prominent role in synaptic plasticity, learning, and memory, the isoform-specific functions of CaMKIIβ remain largely unexplored. Yet, perturbation of CaMKIIβ expression, in particular, has been associated with multiple neuropsychiatric diseases, highlighting CaMKIIβ as a gene of interest [see for examples Akita et al., Ann Clin Transl Neurol. 2018; Novak et al., Synapse 59, 61-8 (2006)].

In this study, we reveal a novel isoform-specific function for CaMKIIβ during the development of the cerebral cortex. By using in utero electroporation, we demonstrate that correct levels of CaMKIIβ are essential for proper radial migration of projection neurons. In particular, we show that CaMKIIβ is a critical element not only for the transition between the multipolar and the bipolar stage but also for the saltatory movement of locomoting neurons, two actions which are dependent on its actin-binding and bundling properties. In addition, our data indicate that a fine-tuned balance between CaMKIIβ and cofilin activities is necessary to ensure proper actin remodeling and migration of cortical neurons. Thus, our findings demonstrate that CaMKIIβ, by regulating the migration of cortical neurons, contributes to normal brain development and further support an important role for this gene in the pathophysiology of neurodevelopmental disorders.

Abstract PubMed
Perturbation of CaMKIIβ expression has been associated with multiple neuropsychiatric diseases, highlighting CaMKIIβ as a gene of interest. Yet, in contrast to CaMKIIα, the specific functions of CaMKIIβ in the brain remain poorly explored. Here, we reveal a novel function for this CaMKII isoform in vivo during neuronal development. By using in utero electroporation, we show that CaMKIIβ is an important regulator of radial migration of projection neurons during cerebral cortex development. Knockdown of CaMKIIβ causes accelerated migration of nascent pyramidal neurons, whereas overexpression of CaMKIIβ inhibits migration, demonstrating that precise regulation of CaMKIIβ expression is required for correct neuronal migration. More precisely, CaMKIIβ controls the multipolar–bipolar transition in the intermediate zone and locomotion in the cortical plate through its actin-binding and -bundling activities. In addition, our data indicate that a fine-tuned balance between CaMKIIβ and cofilin activities is necessary to ensure proper migration of cortical neurons. Thus, our findings define a novel isoform-specific function for CaMKIIβ, demonstrating that CaMKIIβ has a major biological function in the developing brain.