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

13 Citations (Scopus)

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
Article number	5903
Journal	Nature Communications
Volume	11
Issue number	1
Pages (from-to)	5903
ISSN	2041-1722
DOIs	https://doi.org/10.1038/s41467-020-19637-5
Publication status	Published - 2020

Keywords

Adult
Aged
Alleles
Amines/metabolism
Animals
Antipsychotic Agents/therapeutic use
Brain/metabolism
Cell Cycle Proteins/genetics
Cilia/metabolism
Drug Resistance/genetics
Genetic Predisposition to Disease/genetics
Humans
Mice
Mice, Knockout
Middle Aged
Mutation
Phenotype
Receptors, Dopamine D2/genetics
Receptors, G-Protein-Coupled/genetics
Schizophrenia/drug therapy
Signal Transduction
Young Adult
Zebrafish

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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), 5903. Article 5903. https://doi.org/10.1038/s41467-020-19637-5

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, pp. 5903. https://doi.org/10.1038/s41467-020-19637-5

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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.",

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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

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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.

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

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Keywords

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