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

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, Richard A. Gibbs, Lawrence Barak, Patrick F. Sullivan, Allison E. Ashley-Koch, Akira Sawa, William C. Wetsel, Thomas Werge and Nicholas Katsanis ()
Additional contact information
Tanner O. Monroe: Northwestern University Feinberg School of Medicine
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
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
Donna M. Muzny: Baylor College of Medicine
Richard A. Gibbs: Baylor College of Medicine
Lawrence Barak: Duke University School of Medicine
Patrick F. Sullivan: University of North Carolina at Chapel Hill
Allison E. Ashley-Koch: Duke Molecular Physiology Institute, Duke University School of Medicine
Akira Sawa: Johns Hopkins University School of Medicine
William C. Wetsel: Duke University School of Medicine
Thomas Werge: University of Copenhagen
Nicholas Katsanis: Northwestern University Feinberg School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19637-5

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