title: Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits.
abstract: Loss-of-function (LOF) mutations in CC2D1A cause a spectrum of neurodevelopmental disorders, including intellectual disability, autism spectrum disorder, and seizures, identifying a critical role for this gene in cognitive and social development. CC2D1A regulates intracellular signaling processes that are critical for neuronal function, but previous attempts to model the human LOF phenotypes have been prevented by perinatal lethality in Cc2d1a-deficient mice. To overcome this challenge, we generated a floxed Cc2d1a allele for conditional removal of Cc2d1a in the brain using Cre recombinase. While removal of Cc2d1a in neuronal progenitors using Cre expressed from the Nestin promoter still causes death at birth, conditional postnatal removal of Cc2d1a in the forebrain via calcium/calmodulin-dependent protein kinase II-alpha (CamKIIa) promoter-driven Cre generates animals that are viable and fertile with grossly normal anatomy. Analysis of neuronal morphology identified abnormal cortical dendrite organization and a reduction in dendritic spine density. These animals display deficits in neuronal plasticity and in spatial learning and memory that are accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming. Cc2d1a conditional knockout mice therefore recapitulate features of both cognitive and social impairment caused by human CC2D1A mutation, and represent a model that could provide much needed insights into the developmental mechanisms underlying nonsyndromic neurodevelopmental disorders.
authors.affiliation: Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Oaks
authors.affiliation: Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Zamarbide
authors.affiliation: Division of Genetics and Genomics and the Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.|Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dimira E
authors.initials: DE
authors.lastname: Tambunan
authors.affiliation: Center for Neural Science, New York University, New York, NY 10003, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Santini
authors.affiliation: Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Di Costanzo
authors.affiliation: Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Pond
authors.affiliation: Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Johnson
authors.affiliation: Department of Psychology, The George Washington University, Washington, DC 20052, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Lin
authors.affiliation: Division of Genetics and Genomics and the Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.|Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dilenny M
authors.initials: DM
authors.lastname: Gonzalez
authors.affiliation: Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Boehler
authors.affiliation: Department of Psychology, The George Washington University, Washington, DC 20052, USA.
authors.forename: Guangying K
authors.initials: GK
authors.lastname: Wu
authors.affiliation: Center for Neural Science, New York University, New York, NY 10003, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
authors.affiliation: Division of Genetics and Genomics and the Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.|Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.affiliation: Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: M Chiara
authors.initials: MC
authors.lastname: Manzini
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000166:cytology*; D016548:Prosencephalon / Q000473:pathology*; D012097:Repressor Proteins / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D012097:Repressor Proteins; C512283:CC2D1A protein, human; C522738:Cc2d1a protein, mouse
keywords: autism; cognitive development; dendritic spines; intellectual disability; long-term plasticity
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