PCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA608720 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11179980.fastq.gz | Fastqsanger.gz | |||
| SRR11179981.fastq.gz | Fastqsanger.gz | |||
| SRR11179982.fastq.gz | Fastqsanger.gz | |||
| SRR11179983.fastq.gz | Fastqsanger.gz | |||
| SRR11179984.fastq.gz | Fastqsanger.gz |
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Project description: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.
2020-07-16 | GSE145915 | GEO
Project description: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.
| S-EPMC7677393 | biostudies-literature
Project description:Cytoplasmic cleavage of IMPA1 3’UTR is necessary for maintaining axon integrity.
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Project description:The 3’ untranslated regions (3’UTRs) of messenger RNAs (mRNA) are non-coding sequences involved in many aspects of mRNA metabolism, including intracellular localisation and translation. Incorrect processing and delivery of mRNA causes severe developmental defects and has been implicated in many neurological disorders. Here, we use deep sequencing to show that in sympathetic neuron axons, the 3’UTRs of many transcripts undergo cleavage, generating isoforms that express the coding sequence with a short 3’UTR, and stable 3’UTR-derived fragments of unknown function. Cleavage of the long 3’UTR of Inositol Monophosphatase 1 ( IMPA1 ), mediated by a protein complex containing the endonuclease Ago2 and the RNA binding protein HuD, generates a translatable isoform that is necessary for maintaining the integrity of sympathetic neuron axons. Thus, our study provides a new mechanism of mRNA metabolism that simultaneously regulates local protein synthesis and generates a yet undescribed class of non-coding RNAs.
2020-12-31 | GSE160025 | GEO
Project description:Dysfunction of motile cilia can impair mucociliary clearance in the airway and result in primary ciliary dyskinesia (PCD), a pediatric syndrome characterized by chronic respiratory infection and bronchiectasis, as well as infertility, laterality defects, and occasionally hydrocephalus due to defects in cilia in other organ systems. We have previously shown that mutations in genes encoding components of the ciliary central pair apparatus (CPA) perturb ciliary motility and result in PCD in mouse models. However, little is known about how epithelial cell types in the ciliary microenvironment of the upper airway respond to defects in ciliary motility and mucociliary clearance. In this study, we have used a single-cell RNA sequencing (scRNA-seq) approach to investigate the effects of ciliary dysfunction on the tracheal epithelial cells from mouse models with mutations in CPA genes Cfap221 (also known as Pcdp1), Cfap54, and Spef2. Expected cell types were identified in the tracheal epithelial samples, including basal cells, suprabasal cells, secretory cells, deuterosomal cells, ciliated cells, tuft cells, ionocytes, and neuroendocrine cells, as well as an unidentified cell type that does not express markers of typical airway cells. The deuterosomal cells were found to exist in two states that differ largely in expression of genes involved in differentiation into the ciliated cell type. Differentially expressed genes (DEGs) were identified for each cell type, and functional enrichment analysis revealed a variety of important cellular functions altered in mutant cells. Overlapping DEGs shed light on general cellular responses to cilia dysfunction, while unique DEGs indicate that some responses may be specific to the individual mutation and ciliary defect. These analyses uncover new information about cellular responses to mucociliary clearance defects in the airway and pathogenesis of PCD.
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Project description:The ciliary body is required for the maintenance of intraocular pressure and immunity as well as vision accommodation. We report a comprehensive cell atlas of human ciliary body from single-cell RNA sequencing (scRNAseq)
2022-10-05 | GSE206026 | GEO
Project description:Cilia and flagella are dynamicallyregulatedduring development and differentiation. Coordination of temporal and spatial transcription regulators are essential for ciliogenesis. We here report that XAP5 and XAP5L are two conserved pairs of antagonistic transcription regulators that control ciliary transcriptional programs during spermatogenesis. Male mice lacking either XAP5 or XAP5L display infertility, as a result of meiotic prophase arrest and sperm cilia malformation, respectively. XAP5 positively regulates the ciliary gene expression by activating the key regulators including FOXJ1 and RFX families during the early stage of spermatogenesis. In contrast, XAP5L negatively regulates the expression of ciliary genes via repressing these ciliary transcription factors during the spermiogenesis stage. Taken together, our data provide new insights into the mechanisms by which temporal and spatial transcription regulators are coordinated to control ciliary transcriptional programs during spermatogenesis.
2023-07-06 | GSE236388 | GEO
Project description:Schizophrenia Targeted Sequencing
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