title: Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling.
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.
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors: Claudia
authors: C
authors: Fuchs
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors: Stefania
authors: S
authors: Trazzi
authors: Health Sciences and Technologies-Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Italy.
authors: Roberta
authors: R
authors: Torricella
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors: Rocchina
authors: R
authors: Viggiano
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors: Marianna
authors: M
authors: De Franceschi
authors: Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
authors: Elena
authors: E
authors: Amendola
authors: Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
authors: Cornelius
authors: C
authors: Gross
authors: Health Sciences and Technologies-Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Italy.
authors: Laura
authors: L
authors: Calzà
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
authors: Renata
authors: R
authors: Bartesaghi
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy. Electronic address: elisabetta.ciani@unibo.it.
authors: Elisabetta
authors: E
authors: Ciani
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049108:Cell Enlargement; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003712:Dendrites / Q000502:physiology*; D018891:Dentate Gyrus / Q000254:growth & development / Q000502:physiology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D018782:Maze Learning / Q000502:physiology; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C533690:CDKL5 protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: AKT/GSK-3β signaling; CDKL5 disorder; Dendritic development; Neurodevelopmental disorders; Neurogenesis impairment; Rett's syndrome