@article{4ffd865ae5444499b26c30b1f104f1d6,
title = "Kctd13 deletion reduces synaptic transmission via increased RhoA",
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.",
author = "Escamilla, {Christine Ochoa} and Irina Filonova and Walker, {Angela K.} and Xuan, {Zhong X.} and Roopashri Holehonnur and Felipe Espinosa and Shunan Liu and Thyme, {Summer B.} and L{\'o}pez-Garc{\'i}a, {Isabel A.} and Mendoza, {Dorian B.} and Noriyoshi Usui and Jacob Ellegood and Eisch, {Amelia J.} and Genevieve Konopka and Lerch, {Jason P.} and Schier, {Alexander F.} and Speed, {Haley E.} and Powell, {Craig M.}",
note = "Funding Information: Acknowledgements This research was supported by National Institutes of Health (NIH) R01HD069560 and R01HD069560-S1, Autism Speaks, The Hartwell Foundation, Ed and Sue Rose Distinguished Professorship in Neurology, gifts from C. Heighten, D. Caudy and BRAINS for Autism (to C.M.P.), Autism Science Foundation (to C.M.P. and C.O.E.), Canadian Institute for Health Research and Ontario Brain Institute (to J.P.L.), NIH 2K02DA023555 and NASA NNX15AE09G (to A.J.E.), Uehara Foundation (to N.U.), NIH MH102603 (to G.K.), NIH K99MH110603 (to S.B.T.), Damon Runyon Cancer Research Foundation (to S.B.T.), Harvard Brain Institute Bipolar Seed Grant (to A.F.S.), and NIH R01HL109525 (to A.F.S). We thank K. R. Tolias for RhoA KO mouse brain and the University of Texas Southwestern Whole Brain Microscopy Facility Funding Information: (WBMF) for assistance with X-gal histology and slide scanning. The WBMF is supported by the Texas Institute for Brain Injury and Repair. Embryonic stem cells were generated by the trans-NIH Knockout Mouse Project (KOMP) from the KOMP Repository (www.komp.org). NIH grants to Velocigene at Regeneron (U01HG004085) and the CSD Consortium (U01HG004080) funded generation of gene-targeted embryonic stem cells for 8,500 genes (KOMP), archived and distributed by the KOMP Repository at the University of California, Davis, and CHORI (U42RR024244).",
year = "2017",
month = nov,
day = "9",
doi = "10.1038/nature24470",
language = "English",
volume = "551",
pages = "227--231",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7679",
}