title: Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice.
abstract: Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy. The biological function of CDKL5 and its role in the etiology of these disorders, however, remain unclear. Here we report the development of a unique knockout mouse model of CDKL5-related disorders and demonstrate that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory. Neurophysiological recordings reveal alterations in event-related potentials (ERPs) similar to those observed in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKT-mammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 regulates signal transduction pathways and mediates autistic-like phenotypes and together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders.
authors.affiliation: Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: I-Ting Judy
authors.initials: IT
authors.lastname: Wang
authors.forename: Megan
authors.initials: M
authors.lastname: Allen
authors.forename: Darren
authors.initials: D
authors.lastname: Goffin
authors.forename: Xinjian
authors.initials: X
authors.lastname: Zhu
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Fairless
authors.forename: Edward S
authors.initials: ES
authors.lastname: Brodkin
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Siegel
authors.forename: Eric D
authors.initials: ED
authors.lastname: Marsh
authors.forename: Julie A
authors.initials: JA
authors.lastname: Blendy
authors.forename: Zhaolan
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001007:Anxiety / Q000150:complications / Q000201:enzymology / Q000503:physiopathology; D001321:Autistic Disorder / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology*; D001522:Behavior, Animal; D004569:Electroencephalography; D005071:Evoked Potentials / Q000502:physiology*; D006948:Hyperkinesis / Q000150:complications / Q000201:enzymology / Q000503:physiopathology; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012640:Seizures / Q000150:complications / Q000503:physiopathology; D015398:Signal Transduction; D012919:Social Behavior; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D020543:Proteome; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C533690:CDKL5 protein, mouse