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Neurobiol Dis. 2014 Oct;70:53-68. doi: 10.1016/j.nbd.2014.06.006. Epub 2014 Jun 18.

Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling.

Author information

1
Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
2
Health Sciences and Technologies-Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Italy.
3
Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
4
Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy. Electronic address: elisabetta.ciani@unibo.it.

Abstract

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and Rett's syndrome-like features. Since the physiological functions of CDKL5 still need to be elucidated, in the current study we took advantage of a new Cdkl5 knockout (KO) mouse model in order to shed light on the role of this gene in brain development. We mainly focused on the hippocampal dentate gyrus, a region that largely develops postnatally and plays a key role in learning and memory. Looking at the process of neurogenesis, we found a higher proliferation rate of neural precursors in Cdkl5 KO mice in comparison with wild type mice. However, there was an increase in apoptotic cell death of postmitotic granule neuron precursors, with a reduction in total number of granule cells. Looking at dendritic development, we found that in Cdkl5 KO mice the newly-generated granule cells exhibited a severe dendritic hypotrophy. In parallel, these neurodevelopmental defects were associated with impairment of hippocampus-dependent memory. Looking at the mechanisms whereby CDKL5 exerts its functions, we identified a central role of the AKT/GSK-3β signaling pathway. Overall our findings highlight a critical role of CDKL5 in the fundamental processes of brain development, namely neuronal precursor proliferation, survival and maturation. This evidence lays the basis for a better understanding of the neurological phenotype in patients carrying mutations in the CDKL5 gene.

KEYWORDS:

AKT/GSK-3β signaling; CDKL5 disorder; Dendritic development; Neurodevelopmental disorders; Neurogenesis impairment; Rett's syndrome

PMID:
24952363
PMCID:
PMC4146476
DOI:
10.1016/j.nbd.2014.06.006
[Indexed for MEDLINE]
Free PMC Article

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