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

TitlePCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia.
Publication TypeJournal Article
Year of Publication2020
AuthorsMonroe, 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
JournalNat Commun
Date Published2020 Nov 19
KeywordsAdult, Aged, Alleles, Amines, Animals, Antipsychotic Agents, Brain, Cell Cycle Proteins, Cilia, Drug Resistance, Genetic Predisposition to Disease, Humans, Mice, Mice, Knockout, Middle Aged, Mutation, Phenotype, Receptors, Dopamine D2, Receptors, G-Protein-Coupled, Schizophrenia, Signal Transduction, Young Adult, Zebrafish

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.

Alternate JournalNat Commun
PubMed ID33214552
PubMed Central IDPMC7677393
Grant ListP50 MH094268 / MH / NIMH NIH HHS / United States
P41 EB015897 / EB / NIBIB NIH HHS / United States
P30 CA060553 / CA / NCI NIH HHS / United States
T32 DK108738 / DK / NIDDK NIH HHS / United States
P20 MH084018 / MH / NIMH NIH HHS / United States

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