Abstract
Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders and are among the most prevalent in autism spectrum disorders. Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes. The function of KCTD13 in the mammalian brain, however, remains unknown. Here we delete the Kctd13 gene in mice and demonstrate reduced synaptic transmission. Reduced synaptic transmission correlates with increased levels of Ras homolog gene family, member A (RhoA), a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to a previous knockdown study, deletion of Kctd13 or kctd13 does not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicate Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarify the role of Kctd13 in neurogenesis and brain size. Our data also reveal a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Autism Spectrum Disorder / genetics
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Autism Spectrum Disorder / psychology
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Autistic Disorder / genetics
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Autistic Disorder / psychology
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Brain / anatomy & histology
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Brain / cytology
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Brain / metabolism*
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Brain / pathology
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CA1 Region, Hippocampal / metabolism
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CA1 Region, Hippocampal / pathology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Chromosome Deletion
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Chromosome Disorders / genetics
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Chromosome Disorders / psychology
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Chromosomes, Human, Pair 16 / genetics
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Cullin Proteins / metabolism
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Female
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Gene Deletion*
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Intellectual Disability / genetics
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Intellectual Disability / psychology
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Male
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Mice
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Multifactorial Inheritance / genetics
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Neurogenesis / genetics
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Organ Size / genetics
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Reproducibility of Results
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Synaptic Transmission / drug effects
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Synaptic Transmission / genetics*
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Ubiquitin-Protein Ligase Complexes
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Zebrafish
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Zebrafish Proteins / genetics
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Zebrafish Proteins / metabolism*
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rho GTP-Binding Proteins / antagonists & inhibitors
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rho GTP-Binding Proteins / metabolism*
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rhoA GTP-Binding Protein
Substances
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Carrier Proteins
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Cul3 protein, mouse
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Cullin Proteins
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Zebrafish Proteins
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kctd13 protein, zebrafish
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PDIP1 protein, mouse
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Ubiquitin-Protein Ligase Complexes
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RhoA protein, mouse
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rho GTP-Binding Proteins
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rhoA GTP-Binding Protein
Supplementary concepts
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16p11.2 Deletion Syndrome