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.

The ciliary impact of nonciliary gene mutations

“…Some proteins of the ciliome assemble together with a set of scaffold proteins into 70-100 nm cytoplasmic granules known as centriolar satellites [14,15]. Centriolar satellites traffic around centrioles in a microtubule-dependent manner and were found to be important for ciliogenesis in some cell line models [16,17], but a PCM1 knockout mouse only displayed defects in long-term cilia maintenance in some brain tissues [18]. Loss of the centriolar satellite scaffold protein PCM1 interferes with the ciliary localization of several proteins.…”

Centriolar satellites expedite mother centriole remodeling to promote ciliogenesis

“…Recently, a mouse Pcm1 gene trap was described ( Monroe et al, 2020 ). Aged mice homozygous for this allele exhibited enlarged brain ventricles, progressive neuronal cilia maintenance defects and late-onset behavioral changes, but without perinatal lethality and other early cilia-associated phenotypes.…”

“…Centriolar satellites are dynamic, change in response to cell stresses, and have been implicated in diverse processes including Hedgehog signaling, autophagy, proteasome activity and aggresome formation ( Holdgaard et al, 2019; Hori and Toda, 2017; Joachim et al, 2017; Kubo and Tsukita, 2003; Lecland and Merdes, 2018; Odabasi et al, 2019; Prosser and Pelletier, 2020; Prosser et al, 2020; Tang et al, 2013; Villumsen et al, 2013; Wang et al, 2013a ). Recent work suggested that PCM1 is critical for maintaining neuronal cilia, disruption of which may cause schizophrenic-like features in aged mice ( Monroe et al, 2020 ). Thus, understanding of the function of PCM1 and centriolar satellites is evolving.…”

Epigenomic Changes after Acupuncture Treatment in Patients Suffering from Burnout

“…2e), regulated the proliferation of neural progenitor cells in mice [51,52]. In humans, PMC1 was found to increase the availability of the dopamine receptor D2 (DRD2) in the brain and associations between PCM1 genetic variants and schizophrenia have been described [53]. The intravenous administration of a synthetic corticotropin-releasing hormone in humans increased both the cortisol stress hormone in blood and dopamine in the dorsal striatum according to positron emission tomography scans per- formed with a dopamine receptor radio-ligand [54].…”