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PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia

Author

Listed:
  • Tanner O. Monroe

    (Northwestern University Feinberg School of Medicine
    Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago)

  • Melanie E. Garrett

    (Duke Molecular Physiology Institute, Duke University School of Medicine)

  • Maria Kousi

    (MIT Computer Science and Artificial Intelligence Laboratory (CSAIL), Broad Institute of MIT and Harvard)

  • Ramona M. Rodriguiz

    (Duke University School of Medicine
    Duke University School of Medicine)

  • Sungjin Moon

    (Kangwon National University)

  • Yushi Bai

    (Duke University School of Medicine)

  • Steven C. Brodar

    (Duke University School of Medicine)

  • Karen L. Soldano

    (Duke Molecular Physiology Institute, Duke University School of Medicine)

  • Jeremiah Savage

    (The University of Chicago)

  • Thomas F. Hansen

    (University of Copenhagen
    MHC Sct. Hans, Mental Health Services)

  • Donna M. Muzny

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Richard A. Gibbs

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Lawrence Barak

    (Duke University School of Medicine)

  • Patrick F. Sullivan

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill
    Karolinska Institutet)

  • Allison E. Ashley-Koch

    (Duke Molecular Physiology Institute, Duke University School of Medicine)

  • Akira Sawa

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • William C. Wetsel

    (Duke University School of Medicine
    Duke University School of Medicine
    Duke University School of Medicine
    Duke University School of Medicine)

  • Thomas Werge

    (University of Copenhagen
    MHC Sct. Hans, Mental Health Services
    iPSYCH - The Lundbeck Foundation Initiative for Integrative Psychiatric Research
    University of Copenhagen)

  • Nicholas Katsanis

    (Northwestern University Feinberg School of Medicine
    Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago)

Abstract

The neuronal primary cilium and centriolar satellites have functions in neurogenesis, but little is known about their roles in the postnatal brain. We show that ablation of pericentriolar material 1 in the mouse leads to progressive ciliary, anatomical, psychomotor, and cognitive abnormalities. RNAseq reveals changes in amine- and G-protein coupled receptor pathways. The physiological relevance of this phenotype is supported by decreased available dopamine D2 receptor (D2R) levels and the failure of antipsychotic drugs to rescue adult behavioral defects. Immunoprecipitations show an association with Pcm1 and D2Rs. Finally, we sequence PCM1 in two human cohorts with severe schizophrenia. Systematic modeling of all discovered rare alleles by zebrafish in vivo complementation reveals an enrichment for pathogenic alleles. Our data emphasize a role for the pericentriolar material in the postnatal brain, with progressive degenerative ciliary and behavioral phenotypes; and they support a contributory role for PCM1 in some individuals diagnosed with schizophrenia.

Suggested Citation

  • Tanner O. Monroe & Melanie E. Garrett & Maria Kousi & Ramona M. Rodriguiz & Sungjin Moon & Yushi Bai & Steven C. Brodar & Karen L. Soldano & Jeremiah Savage & Thomas F. Hansen & Donna M. Muzny & Richa, 2020. "PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19637-5
    DOI: 10.1038/s41467-020-19637-5
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