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Modeling OTUD7A loss-of-function mutation in schizophrenia-associated 15q13.3 microdeletion in human neurons

ABSTRACT: Modeling OTUD7A loss-of-function mutation in schizophrenia-associated 15q13.3 microdeletion in human neurons

PROVIDER: PRJNA783895 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17045228_1.fastq.gz	Fastqsanger.gz
	SRR17045228_2.fastq.gz	Fastqsanger.gz
	SRR17045229_1.fastq.gz	Fastqsanger.gz
	SRR17045229_2.fastq.gz	Fastqsanger.gz
	SRR17045230_1.fastq.gz	Fastqsanger.gz

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Modeling OTUD7A loss-of-function mutation in schizophrenia-associated 15q13.3 microdeletion in human neurons

Project description:The edited lines introduced a premature termination at rs757148409/p.Arg89Ter. The mutant iNs showed a ~50% decrease in OTUD7A protein expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, synaptic puncta density of AMPA receptor subunit GluA1 and postsynaptic scaffold PSD-95, as well as neural firing rate and network activity. Congruent with the neural phenotypic alterations in mutant iNs, our transcriptomic analysis showed that the set of OTUD7A LoF downregulated genes was significantly enriched for synapse development and function, and was associated with SZ and other neuropsychiatric disorders. These results suggest that the OTUD7A LoF mutation rs757148409 impairs neurodevelopment and synaptic function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 microdeletion.

2021-11-28 | GSE189614 | GEO

Network effects of the 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

Project description:Background: Deletions in the 15q13.3 region are associated with several neuropsychiatric disorders, including autism and schizophrenia. Association studies in humans and functional studies in mice have suggested that several genes within the 15q13.3 microdeletion may play a role in neuronal dysfunction, but the intermediate molecular mechanisms remain unknown. Methods: Induced pluripotent stem cells from 3 patients with the 15q13.3 microdeletion and 3 sex-matched controls were generated and converted into induced neurons. We analyzed the genome-wide effects of the 15q13.3 microdeletion on gene expression, DNA methylation, chromatin accessibility, and sensitivity to cisplatin-induced DNA damage. We also evaluated gene expression changes in induced neurons containing CRISPR knockouts of single 15q13.3 microdeletion genes. Results: In both cell types, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Further, we observed global effects of the microdeletion on the transcriptome and epigenome, with disruptions in several neuropsychiatric disorder-associated pathways, such as Wnt signaling, ribosome biogenesis, DNA binding, and cell adhesion. Conclusions: Our multi-omics analyses of the 15q13.3 microdeletion revealed downstream effects in pathways previously associated with neuropsychiatric disorders. This molecular systems analysis can also be applied to other brain relevant chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders.

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Thalamocortical organoids reveal axonogenesis phenotypes of 22q11.2 microdeletion [scRNA-seq]

Project description:Dysfunction of the thalamocortical pathway has been implicated in multiple psychiatric disorders, but mechanisms by which these defects emerge remain poorly understood. We explored this question in the context of the 22q11.2 microdeletion, which represents a significant genetic risk for schizophrenia, leveraging emerging technologies of in vitro brain organogenesis using chimeric brain organoids derived from human induced pluripotent stem cells. Here we show that the 22q11.2 microdeletion leads to transcriptional dysregulation in thalamic organoids that is enriched for psychiatric disease risk genes, including elevated expression of FOXP2, which represents the most significantly dysregulated transcription factor in glutamatergic neurons and astroctyes. In a co-culture model fusing thalamic and cortical organoids, we demonstrate that the 22q11.2 deletion mediates an overgrowth of thalamic axons via overexpression of FOXP2, which then subsequently mediates the overgrowth of reciprocal corticothalamic axons. Dysregulation of FOXP2 leads to downregulation of ROBO2, an axon repulsive receptor important for thalamocortical axon pathfinding, and knockdown of ROBO2 in control organoids phenocopies excessive outgrowth of thalamic axons. Together, our study suggests that early steps in thalamocortical pathway development may be dysregulated in a model of genetic risk for schizophrenia, and contribute to neural phenotypes in 22q11.2 microdeletion syndrome.

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Schizophrenia-related microdeletion causes progressive brain ventricle enlargement through microRNA-dependent deceleration of motile cilia beating

Project description:Schizophrenia-related microdeletion causes progressive brain ventricle enlargement through microRNA-dependent deceleration of motile cilia beating

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Modeling Synaptic Mechanisms of Autism-associated Neuroligin-3 R451C Mutation Using Human Neurons

Project description:Modeling Synaptic Mechanisms of Autism-associated Neuroligin-3 R451C Mutation Using Human Neurons

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Schizophrenia-related microdeletion causes progressive brain ventricle enlargement through microRNA-dependent deceleration of motile cilia beating

Project description:Progressive ventricular enlargement is one of the most reproducible and recognizable structural abnormalities in schizophrenia, and is associated with more severe symptoms and poorer clinical outcome. The mechanisms of ventricular enlargement in schizophrenia is unknown. We identified that progressive ventricular enlargement is associated with deceleration of motile cilia beating in ependymal cells lining ventricular walls in murine models of schizophrenia-associated 22q11 deletion syndrome (22q11DS). The cilia beating deficit is caused by an aberrant elevation of Drd1, which is highly enriched in the motile cilia. Haploinsufficiency of the microRNA-processing gene Dgcr8 is responsible for the Drd1 elevation in ependymal cells of 22q11DS mice, and is mediated by reduction of Drd1-targeting microRNAs miR-674-3p and miR-382-3p. Replenishing miR-674-3p or miR-382-3p in 22q11DS mice rescued the motile cilia beating abnormalities and normalized the ventricular size. Knockdown of these microRNA mimicked cilia beating and ventricular deficits. Ventricular enlargement was also caused by Crispr/cas9-mediated deletion of the Drd1 seed site for miR-674-3p/miR-382-3p. This suggests that Dgcr8-miR-674-3p/miR-382-3p-Drd1–dependent disruption of cilia motility in ependymal cells is a pathogenic event underlying schizophrenia-associated ventricular enlargement.

2019-12-07 | GSE123560 | GEO

Mice modeling human CNVs associated with psychiatric disorders

Project description:139 samples from cortex and hipocampus of the mice modeling human CNVs associatted with schizophrenia: Df(h15q13)/+, Df(h15q13)/-, Df(h22q11)/+, and Df(h1q21)/+

2019-05-01 | GSE129891 | GEO

A novel 13q12 microdeletion associated with familial syndromic corneal dystropy

Project description:We identified a family with a novel chromosome 13 microdeletion associated with a syndromic form of corneal opacification. In order to determine which genes in/around the microdeletion were contributing to the constellation of phenotypes, a corneal epithelial sample was obtained during a superficial keratectomy of the proband's 9-year-old brother.

2023-08-11 | GSE230430 | GEO

Molecular profile of parvalbumin-immunoreactive neurons in superior temporal cortex in schizophrenia

Project description:Dysregulation of pyramidal cell network function by the soma- and axon-targeting inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) represents a core pathophysiological feature of schizophrenia. In order to gain insight into the molecular basis of their functional impairment, we used laser capture microdissection (LCM) to isolate PV-immunolabeled neurons from layer 3 of BrodmannM-bM-^@M-^Ys area 42 of the superior temporal gyrus (STG) from postmortem schizophrenia and normal control brains. We then extracted ribonucleic acid (RNA) from these neurons and determined their messenger RNA (mRNA) expression profile using the Affymetrix platform of microarray technology. 739 mRNA transcripts were found to be differentially expressed in PV neurons in subjects with schizophrenia, including genes associated with WNT (wingless-type), NOTCH and PGE2 (prostaglandin E2) signaling, in addition to genes that regulate cell cycle and apoptosis. Of these 739 genes, only 89 (12%) were also differentially expressed in pyramidal neurons as found in the accompanying study, suggesting that the molecular pathophysiology of schizophrenia appears to be predominantly neuronal type-specific. Taken together, findings of this study provide a neurobiological framework within which hypotheses of the molecular mechanisms that underlie the dysfunction of PV neurons in schizophrenia can be generated and experimentally explored and, as such, may ultimately inform the conceptualization of targeted molecular intervention. Gene expression microarray from mRNA isolated from parvalbumin cells in layer 3 of the STG from 8 normal controls and 8 subjects with schizophrenia. There was no significant difference between diagnosis groups for age, sex, and post mortem interval (PMI).

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Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis

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