Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders1,2,3,4,5,6 and are among the most prevalent in autism spectrum disorders1,2,7. Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes8,9. 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 study8, 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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  1. 1.

    et al. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 17, 628–638 (2008)

  2. 2.

    et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008)

  3. 3.

    et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat. Genet. 41, 1223–1227 (2009)

  4. 4.

    et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J. Med. Genet. 47, 332–341 (2010)

  5. 5.

    et al. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J. Med. Genet. 49, 660–668 (2012)

  6. 6.

    et al. Common variant at 16p11.2 conferring risk of psychosis. Mol. Psychiatry 19, 108–114 (2014)

  7. 7.

    et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008)

  8. 8.

    et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 485, 363–367 (2012)

  9. 9.

    et al. Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13-Cul3-RhoA pathway in psychiatric diseases. Neuron 85, 742–754 (2015)

  10. 10.

    et al. Association and mutation analyses of 16p11.2 autism candidate genes. PLoS ONE 4, e4582 (2009)

  11. 11.

    & Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol. 14, 1109–1120 (2015)

  12. 12.

    et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014)

  13. 13.

    et al. Narrowing the critical deletion region for autism spectrum disorders on 16p11.2. Am. J. Med. Genet B 156, 243–245 (2011)

  14. 14.

    , , , & The BTB domain, found primarily in zinc finger proteins, defines an evolutionarily conserved family that includes several developmentally regulated genes in Drosophila. Proc. Natl Acad. Sci. USA 91, 10717–10721 (1994)

  15. 15.

    et al. Cullin mediates degradation of RhoA through evolutionarily conserved BTB adaptors to control actin cytoskeleton structure and cell movement. Mol. Cell 35, 841–855 (2009)

  16. 16.

    et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014)

  17. 17.

    et al. Differential effects of Rho GTPases on axonal and dendritic development in hippocampal neurones. J. Neurochem. 90, 9–18 (2004)

  18. 18.

    & Rho GTPases and activity-dependent dendrite development. Curr. Opin. Neurobiol. 14, 297–304 (2004)

  19. 19.

    et al. The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. Nat. Neurosci. 7, 364–372 (2004)

  20. 20.

    , & Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho. Cereb. Cortex 10, 927–938 (2000)

  21. 21.

    , & Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons. J. Neurosci. 20, 5329–5338 (2000)

  22. 22.

    , , , & Essential roles of Drosophila RhoA in the regulation of neuroblast proliferation and dendritic but not axonal morphogenesis. Neuron 25, 307–316 (2000)

  23. 23.

    , & Rho GTPases regulate distinct aspects of dendritic arbor growth in Xenopus central neurons in vivo. Nat. Neurosci. 3, 217–225 (2000)

  24. 24.

    et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168–176 (2007)

  25. 25.

    , & The probability of transmitter release at a mammalian central synapse. Nature 366, 569–572 (1993)

  26. 26.

    et al. Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases. Chem. Biol. 19, 699–710 (2012)

  27. 27.

    et al. Small-molecule inhibitors targeting G-protein-coupled Rho guanine nucleotide exchange factors. Proc. Natl Acad. Sci. USA 110, 3155–3160 (2013)

  28. 28.

    , & Rho-modifying C3-like ADP-ribosyltransferases. Rev. Physiol. Biochem. Pharmacol. 152, 1–22 (2004)

  29. 29.

    et al. Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPARγ and RhoA/Rho-kinase. Cell Metab. 16, 462–472 (2012)

  30. 30.

    et al. Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons. Neural Dev. 11, 7 (2016)

  31. 31.

    , & Sexual dimorphism revealed in the structure of the mouse brain using three-dimensional magnetic resonance imaging. Neuroimage 35, 1424–1433 (2007)

  32. 32.

    , , & Variations in post-perfusion immersion fixation and storage alter MRI measurements of mouse brain morphometry. Neuroimage 142, 687–695 (2016)

  33. 33.

    , , & In vivo multiple-mouse MRI at 7 Tesla. Magn. Reson. Med. 54, 1311–1316 (2005)

  34. 34.

    , & MRI phenotyping of genetically altered mice. Methods Mol. Biol. 711, 349–361 (2011)

  35. 35.

    , & Partitioning k-space for cylindrical three-dimensional rapid acquisition with relaxation enhancement imaging in the mouse brain. NMR Biomed. 30, 1099–1492 (2017)

  36. 36.

    , , , & Anatomical phenotyping in the brain and skull of a mutant mouse by magnetic resonance imaging and computed tomography. Physiol. Genomics 24, 154–162 (2006)

  37. 37.

    et al. Automated deformation analysis in the YAC128 Huntington disease mouse model. Neuroimage 39, 32–39 (2008)

  38. 38.

    , , , & High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice. Neuroimage 42, 60–69 (2008)

  39. 39.

    , , , & A segmentation protocol and MRI atlas of the C57BL/6J mouse neocortex. Neuroimage 78, 196–203 (2013)

  40. 40.

    et al. Genetic effects on cerebellar structure across mouse models of autism using a magnetic resonance imaging atlas. Autism Res. 7, 124–137 (2014)

  41. 41.

    , & Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage 15, 870–878 (2002)

  42. 42.

    In vivo electroporation in the embryonic mouse central nervous system. Nat. Protocols 1, 1552–1558 (2006)

  43. 43.

    et al. Selective and regulated gene expression in murine Purkinje cells by in utero electroporation. Eur. J. Neurosci. 36, 2867–2876 (2012)

  44. 44.

    et al. High-performance and site-directed in utero electroporation by a triple-electrode probe. Nat. Commun. 3, 960 (2012)

  45. 45.

    et al. Fate-restricted neural progenitors in the mammalian cerebral cortex. Science 337, 746–749 (2012)

  46. 46.

    , & The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice. Science 342, 987–991 (2013)

  47. 47.

    , , & Neuronal subtype specification in the cerebral cortex. Nat. Rev. Neurosci. 8, 427–437 (2007)

  48. 48.

    , , & Estimation of the number of somatostatin neurons in the striatum: an in situ hybridization study using the optical fractionator method. J. Comp. Neurol. 370, 11–22 (1996)

  49. 49.

    et al. Efficient mutagenesis by Cas9 protein-mediated oligonucleotide insertion and large-scale assessment of single-guide RNAs. PLoS ONE 9, e98186 (2014)

  50. 50.

    , , , & nacre encodes a zebrafish microphthalmia-related protein that regulates neural-crest-derived pigment cell fate. Development 126, 3757–3767 (1999)

  51. 51.

    et al. Whole-brain activity mapping onto a zebrafish brain atlas. Nat. Methods 12, 1039–1046 (2015)

  52. 52.

    et al. Preparation of PCR-quality mouse genomic DNA with hot sodium hydroxide and tris (HotSHOT). Biotechniques 29, 52, 54 (2000)

  53. 53.

    , , & Object exploration and reactions to spatial and nonspatial changes in hooded rats following damage to parietal cortex or hippocampal formation. Behav. Neurosci. 106, 447–456 (1992)

  54. 54.

    et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav. 3, 287–302 (2004)

  55. 55.

    et al. Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav. 3, 303–314 (2004)

  56. 56.

    et al. The presynaptic active zone protein RIM1α is critical for normal learning and memory. Neuron 42, 143–153 (2004)

  57. 57.

    , & The role of hippocampal subregions in detecting spatial novelty. Behav. Neurosci. 119, 145–153 (2005)

  58. 58.

    et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71–76 (2007)

  59. 59.

    et al. Increased anxiety-like behavior in mice lacking the inhibitory synapse cell adhesion molecule neuroligin 2. Genes Brain Behav. 8, 114–126 (2009)

  60. 60.

    , , & Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc. Natl Acad. Sci. USA 106, 17998–18003 (2009)

  61. 61.

    et al. Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J. Neurosci. 30, 2115–2129 (2010)

  62. 62.

    , , & RIM1α and interacting proteins involved in presynaptic plasticity mediate prepulse inhibition and additional behaviors linked to schizophrenia. J. Neurosci. 30, 5326–5333 (2010)

  63. 63.

    & Nonrigid image registration in shared-memory multiprocessor environments with application to brains, breasts, and bees. IEEE Trans. Inf. Technol. Biomed. 7, 16–25 (2003)

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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 (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).

Author information

Author notes

    • Irina Filonova
    • , Noriyoshi Usui
    •  & Amelia J. Eisch

    Present addresses: Faculty Affairs Office, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa, Japan 904-0495 (I.F.); Division of Development of Mental Functions, Research Center for Child Mental Development, University of Fukui, Fukui 910-1193, Japan; Division of Developmental Higher Brain Functions, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka 565-0871, Japan (N.U.); Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104-4318, USA (A.J.E.); Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-4318, USA (A.J.E.).

    • Christine Ochoa Escamilla
    •  & Irina Filonova

    These authors contributed equally to this work.


  1. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, USA

    • Christine Ochoa Escamilla
    • , Irina Filonova
    • , Angela K. Walker
    • , Zhong X. Xuan
    • , Roopashri Holehonnur
    • , Felipe Espinosa
    • , Shunan Liu
    • , Isabel A. López-García
    • , Dorian B. Mendoza
    • , Haley E. Speed
    •  & Craig M. Powell
  2. Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Summer B. Thyme
    •  & Alexander F. Schier
  3. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Noriyoshi Usui
    • , Genevieve Konopka
    •  & Craig M. Powell
  4. Mouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada

    • Jacob Ellegood
    •  & Jason P. Lerch
  5. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Amelia J. Eisch
    •  & Craig M. Powell
  6. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1X8, Canada

    • Jason P. Lerch
  7. Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, USA

    • Alexander F. Schier
  8. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Alexander F. Schier
  9. Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA

    • Alexander F. Schier
  10. FAS Center for Systems Biology, Harvard University, Harvard, Massachusetts 02138, USA

    • Alexander F. Schier


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C.O.E., I.F., S.B.T., J.E. and C.M.P. designed the study and wrote the paper. All authors edited and approved the manuscript. Z.X.X. generated, confirmed, and genotyped mice with aid from S.L. C.O.E. performed/analysed data for field and whole-cell electrophysiology, biochemistry, and field electrophysiology with rhosin and C3. F.E. performed/analysed MK-801 whole-cell electrophysiology. H.E.S. performed whole-cell electrophysiology with rhosin, miniature inhibitory postsynaptic currents (mIPSCs), and cortical mEPSCs. C.O.E. analysed the data. I.A.L. contributed to biochemistry. I.F. performed biochemistry, immunohistochemistry, and neurogenesis with supervision by A.J.E. I.F. and A.K.W. performed embryonic neurogenesis and A.K.W. analysed the data with consultation by A.J.E. N.U. performed IUE supervised by G.K., I.F. sectioned and stained tissue, and A.K.W. analysed data. I.F. performed cortical layer staining, and R.H. and D.B.M. analysed data. S.B.T. performed zebrafish studies with supervision by A.F.S. J.E. performed and analysed mouse MRI experiments supervised by J.P.L.

Competing interests

C.M.P. has accepted travel funds/honoraria to speak once at the following companies: Psychogenics; Astra-Zeneca; Roche; Pfizer; and Dainippon Sumitomo Pharma Co. C.M.P. has an investigator-initiated Novartis grant for clinical research. None of these relates to the current study.

Corresponding author

Correspondence to Craig M. Powell.

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