ZFIN ID: ZDB-PUB-201121-3
PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia
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.
Date: 2020
Source: Nature communications   11: 5903 (Journal)
Registered Authors: Katsanis, Nicholas
Keywords: none
MeSH Terms:
  • Adult
  • Aged
  • Alleles
  • Amines/metabolism
  • Animals
  • Antipsychotic Agents/therapeutic use
  • Brain/metabolism
  • Brain/pathology
  • Brain/physiopathology
  • Cell Cycle Proteins/genetics
  • Cell Cycle Proteins/metabolism
  • Cell Cycle Proteins/physiology*
  • Cilia/metabolism
  • Cilia/pathology*
  • Drug Resistance/genetics
  • Genetic Predisposition to Disease/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/genetics*
  • Schizophrenia/pathology
  • Schizophrenia/physiopathology
  • Signal Transduction
  • Young Adult
  • Zebrafish
PubMed: 33214552 Full text @ Nat. Commun.
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.