Kctd13 deletion reduces synaptic transmission via increased RhoA
Open accessAbstract
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.
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These findings do not generalize to mice: two follow-up studies reported normal brain size in Kctd13-deficient mice.
“However, these findings do not generalize to mice: two follow-up studies reported normal brain size in Kctd13-deficient mice [82, 83].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [82]
Kctd13-deficient mice display reduced dendritic length/complexity and spine density, which is linked to downstream RhoA overexpression.
“Kctd13-deficient mice display reduced dendritic length/complexity and spine density, which is linked to downstream RhoA overexpression [82].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [82]
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<i>KCTD</i>: A new gene family involved in neurodevelopmental and neuropsychiatric disorders
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- Authors
- Escamilla, C. O., Filonova, I., Walker, A. K., Xuan, Z. X., Holehonnur, R., Espinosa, F., Liu, S., Thyme, S. B., López-García, I. A., Mendoza, D. B., Usui, N., Ellegood, J., Eisch, A. J., Konopka, G., Lerch, J. P., Schier, A. F., Speed, H. E., & Powell, C. M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Harvard University (US)
- Hospital for Sick Children (CA)
- University of Toronto (CA)
- Broad Institute (US)
- Corresponding author
- Powell, Craig M.
- ORCID
- Venue
- Nature
- Published
- 2017-11
- Volume
- 551
- Issue
- 7679
- Pages
- 227-231
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5787033
- OpenAlex
- W2765981931
- Cited by
- 165
- References
- 11
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 19 · 2023: 21 · 2022: 20 · 2021: 27 · 2020: 19 · 2019: 19 · 2018: 12 · 2017: 1
- FWCI
- 9.26
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL109525)
- National Institute of Mental Health (R01MH102603, K99MH110603, R01MH093697)
- National Institute on Drug Abuse (K02DA023555)
- National Human Genome Research Institute (U01HG004085, U01HG004080)
- National Center for Research Resources (U42RR024244)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD069560)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- RhoA, synaptic transmission, autism spectrum disorder, gene deletion, brain development, brain size, neurogenesis, neuropsychiatric disorders, therapeutic target, zebrafish, mouse model, social behavior
- MeSH terms
- Autism Spectrum Disorder, Animals, Autistic Disorder, Brain, Carrier Proteins, Chromosome Deletion, Chromosomes, Human, Pair 16, Female, Male, Intellectual Disability, Synaptic Transmission, Organ Size, Zebrafish, Reproducibility of Results, Gene Deletion, Multifactorial Inheritance, rho GTP-Binding Proteins, rhoA GTP-Binding Protein, Chromosome Disorders, Zebrafish Proteins, Ubiquitin-Protein Ligase Complexes, Cullin Proteins, Mice, Neurogenesis, CA1 Region, Hippocampal
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