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; Nicholas Katsanis

doi:10.1038/s41467-020-19637-5

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, Nicholas Katsanis^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Article number	5903
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19637-5
State	Published - Dec 2020

Funding

We thank Dr. Edwin Oh for initiating the project and contributing to several experiments, E. Golden, K. Childs, and K. Bendt for assistance with mouse husbandry, J. Crowley and R. Nonneman for assistance with haloperidol dosing, and T. Rhodes and C. Means for conducting behavioral experiments and pharmacology in the Mouse Behavioral and Neuroendocrine Analysis Core Facility at Duke University. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Some of the equipment and software used in the behavioral studies were purchased with a grant from the North Carolina Biotechnology Center. Magnetic resonance imaging was performed at the Duke Center for In Vivo Microscopy and the NIH/NIBIB National Biomedical Technology Resource Center (P41 EB015897). This work was supported by NIH grants: 5T32DK108738-04 (T.O.M.), U54 HG002373 (R.A.G.), Silvo O. Conte Center grant MH084018 (N.K. and A.S.). N.K. holds the Valerie and George D. Kennedy Professorship in Human Genetics. Investigators were blinded to genotype.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-020-19637-5

Cite this

Monroe, T. O., Garrett, M. E., Kousi, M., Rodriguiz, R. M., Moon, S., Bai, Y., Brodar, S. C., Soldano, K. L., Savage, J., Hansen, T. F., Muzny, D. M., Gibbs, R. A., Barak, L., Sullivan, P. F., Ashley-Koch, A. E., Sawa, A., Wetsel, W. C., Werge, T., & Katsanis, N. (2020). PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia. Nature communications, 11(1), Article 5903. https://doi.org/10.1038/s41467-020-19637-5

@article{116b980c76a54dbb924fba1c176e9386,

title = "PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia",

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.",

author = "Monroe, {Tanner O.} and Garrett, {Melanie E.} and Maria Kousi and Rodriguiz, {Ramona M.} and Sungjin Moon and Yushi Bai and Brodar, {Steven C.} and Soldano, {Karen L.} and Jeremiah Savage and Hansen, {Thomas F.} and Muzny, {Donna M.} and Gibbs, {Richard A.} and Lawrence Barak and Sullivan, {Patrick F.} and Ashley-Koch, {Allison E.} and Akira Sawa and Wetsel, {William C.} and Thomas Werge and Nicholas Katsanis",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

doi = "10.1038/s41467-020-19637-5",

language = "English (US)",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Monroe, TO, Garrett, ME, Kousi, M, Rodriguiz, RM, Moon, S, Bai, Y, Brodar, SC, Soldano, KL, Savage, J, Hansen, TF, Muzny, DM, Gibbs, RA, Barak, L, Sullivan, PF, Ashley-Koch, AE, Sawa, A, Wetsel, WC, Werge, T & Katsanis, N 2020, 'PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia', Nature communications, vol. 11, no. 1, 5903. https://doi.org/10.1038/s41467-020-19637-5

TY - JOUR

T1 - PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia

AU - Monroe, Tanner O.

AU - Garrett, Melanie E.

AU - Kousi, Maria

AU - Rodriguiz, Ramona M.

AU - Moon, Sungjin

AU - Bai, Yushi

AU - Brodar, Steven C.

AU - Soldano, Karen L.

AU - Savage, Jeremiah

AU - Hansen, Thomas F.

AU - Muzny, Donna M.

AU - Gibbs, Richard A.

AU - Barak, Lawrence

AU - Sullivan, Patrick F.

AU - Ashley-Koch, Allison E.

AU - Sawa, Akira

AU - Wetsel, William C.

AU - Werge, Thomas

AU - Katsanis, Nicholas

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85096345816&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85096345816&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-19637-5

DO - 10.1038/s41467-020-19637-5

M3 - Article

C2 - 33214552

AN - SCOPUS:85096345816

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5903

ER -

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

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this