1. PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia.
- Author
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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, and Katsanis N
- Subjects
- Adult, Aged, Alleles, Amines metabolism, Animals, Antipsychotic Agents therapeutic use, Brain metabolism, Brain pathology, Brain physiopathology, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cilia metabolism, Drug Resistance genetics, Humans, Mice, Mice, Knockout, Middle Aged, Mutation, Phenotype, Receptors, Dopamine D2 genetics, Receptors, Dopamine D2 metabolism, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Schizophrenia drug therapy, Schizophrenia pathology, Schizophrenia physiopathology, Signal Transduction, Young Adult, Zebrafish, Cell Cycle Proteins physiology, Cilia pathology, Genetic Predisposition to Disease genetics, Schizophrenia genetics
- 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.
- Published
- 2020
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