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DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling

Molecular Psychiatry volume 23, pages 467–475 (2018)Cite this article

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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.

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Acknowledgements

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).

Author information

Author notes

  1. K A Mulligan

    Present address: 14Current address: Department of Biological Sciences, California State University, Sacramento, Sacramento, CA, USA.,

  2. P-M Martin and R E Stanley: These two authors contributed equally to this work.

  3. A P Ross and A E Freitas: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA

    P-M Martin, R E Stanley, A P Ross, A E Freitas, A C Brumback, J Iafrati, K S Stapornwongkul, S Dominguez, S Kivimäe, K A Mulligan, S J Sanders, V S Sohal & B N R Cheyette

  2. TETRAD Graduate Program, University of California San Francisco (UCSF), San Francisco, CA, USA

    R E Stanley & B N R Cheyette

  3. Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA

    C E Moyer & Y Zuo

  4. Division of Child Neurology, Department of Neurology, University of California San Francisco (UCSF), San Francisco, CA, USA

    A C Brumback

  5. Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    M Pirooznia

  6. Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, NY, USA

    W R McCombie

  7. Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA

    J B Potash

  8. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    P P Zandi

  9. Department of Psychiatry and Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    S M Purcell

  10. UCSF Weill Institute for Neurosciences, University of California San Francisco (UCSF), San Francisco, CA, USA

    S J Sanders, V S Sohal & B N R Cheyette

  11. Kavli Institute for Fundamental Neuroscience, University of California San Francisco (UCSF), San Francisco, CA, USA

    V S Sohal & B N R Cheyette

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  1. P-M Martin
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  2. R E Stanley
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Correspondence to B N R Cheyette.

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Martin, PM., Stanley, R., Ross, A. et al. DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling. Mol Psychiatry 23, 467–475 (2018). https://doi.org/10.1038/mp.2016.184

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