@article{a462c4c0588d4ca5ad116765357241af,
title = "DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling",
abstract = "Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/β-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals' brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a glycogen synthase kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single-nucleotide variants (SNVs) in these individuals compared with psychiatrically unaffected controls. Many of these SNVs alter Wnt/β-catenin signaling activity of the neurally predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/β-catenin pathway.",
author = "Martin, {P. M.} and Stanley, {R. E.} and Ross, {A. P.} and Freitas, {A. E.} and Moyer, {C. E.} and Brumback, {A. C.} and J. Iafrati and Stapornwongkul, {K. S.} and S. Dominguez and S. Kivim{\"a}e and Mulligan, {K. A.} and M. Pirooznia and McCombie, {W. R.} and Potash, {J. B.} and Zandi, {P. P.} and Purcell, {S. M.} and Sanders, {S. J.} and Y. Zuo and Sohal, {V. S.} and Cheyette, {B. N.R.}",
note = "Funding Information: This work was supported by grants from SFARI (Grant 329269 to BNRC and Undergraduate Summer Research Award to SD/BNRC), a NARSAD Independent Investigator Award (to BNRC), NIMH T32 No. 5T32MH089920 (to KAM/BNRC and APR/BNRC) and NICHD R01 supplement R01HD55300-S (to RES/BNRC), Brazilian National Council for Scientific and Technological Development grant 248426/2013-3 (to AEF/BNRC), the UCSF Department of Psychiatry (to BNRC, VSS) and NIMH R01MH104227, R01MH094449 and NINDS R01NS078791 (to YZ). The ARRA ASD Sequencing Collaborative provided sequence data sets accessible from dbGaP at http://www. ncbi.nlm.nih.gov/gap through dbGaP accession number phs000298.v1.p1, under dbGAP Research Project No. 5694: 'Analysis of Wnt signaling pathway gene variants in ASD and Scz'. The Bipolar Disorder Exome work was supported by NIMH R01MH087979 (to JBP), R01MH087992 (to WRM) and K01MH093809 (to MP) with additional contributors: Melissa Kramer, Jennifer Parla, Eric T Monson, Fernando S Goes, Marie Breen and Virginia L Willour. We thank P Minasi for technical assistance and XY Yang, G Patil, D Vogt and EL Pai for their support in the Cheyette and neighboring Rubenstein labs. Confocal microscopy was performed at the Nikon Imaging Center (California Institute for Quantitative Biosciences, University of California San Francisco, San Francisco, CA, USA) with advice from Kurt Thorn. BNRC is grateful for mentorship from S Lawrence Zipursky (UCLA) and Randall T Moon (UW), and encouragement from David E Krantz (UCLA), John LR Rubenstein (UCSF) and Samuel H Barondes (UCSF). Funding Information: This work was supported by grants from SFARI (Grant 329269 to BNRC and Undergraduate Summer Research Award to SD/BNRC), a NARSAD Independent Investigator Award (to BNRC), NIMH T32 No. 5T32MH089920 (to KAM/BNRC and APR/ BNRC) and NICHD R01 supplement R01HD55300-S (to RES/BNRC), Brazilian National Council for Scientific and Technological Development grant 248426/2013-3 (to AEF/ BNRC), the UCSF Department of Psychiatry (to BNRC, VSS) and NIMH R01MH104227, R01MH094449 and NINDS R01NS078791 (to YZ). The ARRA ASD Sequencing Collaborative provided sequence data sets accessible from dbGaP at http://www. ncbi.nlm.nih.gov/gap through dbGaP accession number phs000298.v1.p1, under dbGAP Research Project No. 5694: {\textquoteleft}Analysis of Wnt signaling pathway gene variants in ASD and Scz{\textquoteright}. The Bipolar Disorder Exome work was supported by NIMH R01MH087979 (to JBP), R01MH087992 (to WRM) and K01MH093809 (to MP) with additional contributors: Melissa Kramer, Jennifer Parla, Eric T Monson, Fernando S Goes, Marie Breen and Virginia L Willour. We thank P Minasi for technical assistance and XY Yang, G Patil, D Vogt and EL Pai for their support in the Cheyette and neighboring Rubenstein labs. Confocal microscopy was performed at the Nikon Imaging Center (California Institute for Quantitative Biosciences, University of California San Francisco, San Francisco, CA, USA) with advice from Kurt Thorn. BNRC is grateful for mentorship from S Lawrence Zipursky (UCLA) and Randall T Moon (UW), and encouragement from David E Krantz (UCLA), John LR Rubenstein (UCSF) and Samuel H Barondes (UCSF). Publisher Copyright: {\textcopyright} 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.",
year = "2018",
month = feb,
day = "1",
doi = "10.1038/mp.2016.184",
language = "English (US)",
volume = "23",
pages = "467--475",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "2",
}