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

ABSTRACT: The neuronal primary cilium and centriolar satellites have established roles in neurogenesis. However, the role of these regions in the postnatal brain is not clear. Here we show that ablation of the pericentriolar material 1 gene (Pcm1) in the mouse leads to enlarged lateral ventricles and behavioral abnormalities in adult but not juvenile animals. Adults have concomitant reductions in cortical mass and altered hippocampal morphology. Cytoanatomical analyses revealed progressive ciliary shortening, most prominently in the CA1 hippocampus, prelimbic cortex, and amygdala, as psychomotor and cognitive function declined. RNAseq of affected regions revealed significant transcriptional changes in amine- and G-protein coupled receptor activity pathways. The physiological relevance of this phenotype was supported by decreased dopamine D2 receptor (D2R) protein levels, and the failure to rescue adult behavioral defects with antipsychotic drugs. Immunoprecipitations showed an association with Pcm1 and D2Rs. Finally, we sequenced PCM1 in two cohorts of humans with severe schizophrenia. Systematic modeling of all discovered rare alleles by in vivo complementation in zebrafish revealed a significant enrichment for pathogenic alleles. Taken together, our data highlight a role for the pericentriolar material in the postnatal brain; they suggest that a progressive degenerative ciliary/centriolar phenotype can induce behavioral defects in mice; and support a contributory role for PCM1 in individuals with severe psychosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE145915 | GEO | 2020/07/16

REPOSITORIES: GEO

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

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