Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA.
Nat Commun. 2020 Nov 19;11(1):5903. doi: 10.1038/s41467-020-19637-5.
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.
中心体周围物质 1 在小鼠中的缺失导致初级纤毛和中心粒卫星逐渐出现结构和功能异常，并伴随认知和运动行为缺陷。RNA 测序结果显示，胺类和 G 蛋白偶联受体信号通路发生变化。该表型的生理相关性得到了多巴胺 D2 受体（D2R）水平降低和抗精神病药物无法挽救成年行为缺陷的支持。免疫沉淀显示与 Pcm1 和 D2R 的关联。最后，我们在两个伴有严重精神分裂症的人类队列中对 PCM1 进行测序。通过斑马鱼体内互补性对所有发现的罕见等位基因进行系统建模，揭示了致病性等位基因的富集。我们的数据强调了中心体周围物质在出生后大脑中的作用，表现为进行性退行性纤毛和行为表型；并支持 PCM1 在一些被诊断为精神分裂症的个体中发挥作用。
