Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling
Open accessAbstract
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.
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CDKL5 is highly expressed in the brain and deficiencies in CDKL5 inhibit the formation of new granular neurons.
“cyclin-dependent kinase-like 5 (CDKL5) is highly expressed in the brain and deficiencies in CDKL5 inhibit the formation of new granular neurons.31”
From Microglia secrete miR-146a-5p-containing exosomes to regulate neurogenesis in depression (2022) · cites this paper as [31]
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Microglia secrete miR-146a-5p-containing exosomes to regulate neurogenesis in depression
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- Authors
- Fuchs, C., Trazzi, S., Torricella, R., Viggiano, R., De Franceschi, M., Amendola, E., Gross, C., Calzà, L., Bartesaghi, R., & Ciani, E.
- Affiliations
- University of Bologna (IT)
- European Molecular Biology Laboratory (IT)
- Corresponding author
- Ciani, Elisabetta
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 70
- Pages
- 53-68
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC4146476
- OpenAlex
- W2049021349
- Cited by
- 138
- References
- 57
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 22 · 2023: 9 · 2022: 13 · 2021: 20 · 2020: 9 · 2019: 12 · 2018: 14 · 2017: 12 · 2016: 7 · 2015: 4 · 2013: 1
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Independent Social Research Foundation
- International Foundation for CDKL5 Research
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- CDKL5, Rett syndrome, brain development, dentate gyrus, dendritic growth, neuronal apoptosis, neural precursor proliferation, Akt/GSK-3β signaling, hippocampal-dependent memory, X-linked neurodevelopmental disorder
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Cell Survival, Cells, Cultured, Dendrites, Female, Male, Neurons, Signal Transduction, Apoptosis, Protein Serine-Threonine Kinases, Mice, Knockout, Maze Learning, Dentate Gyrus, Glycogen Synthase Kinase 3, Cell Enlargement, Proto-Oncogene Proteins c-akt, Neurogenesis, Neural Stem Cells
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