Elevated endogenous GDNF levels associate with schizophrenia in humans and mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA684069 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13238100.fastq.gz | Fastqsanger.gz | |||
| SRR13238101.fastq.gz | Fastqsanger.gz | |||
| SRR13238102.fastq.gz | Fastqsanger.gz | |||
| SRR13238103.fastq.gz | Fastqsanger.gz | |||
| SRR13238104.fastq.gz | Fastqsanger.gz |
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Project description:Recent studies have identified presynaptic increase in striatal dopamine as the primary dopaminergic abnormality in schizophrenia, responsible for changes in cortical dopamine function in schizophrenic individuals. However, increased dopamine synthesis and release are not recapitulated in existing mouse models, limiting studies on disease progression and potential treatments. We found that the levels of glial cell line-derived neurotrophic factor (GDNF), a strong dopamine system modulator, are increased in the cerebrospinal fluid of first episode psychosis patients. Using a novel strategy to conditionally increase endogenous gene expression, we developed a mouse model with timed elevation of endogenous GDNF. Conditional ‘Knock Up’ of endogenous GDNF expression (GDNF cKU) in the central nervous system at midgestation resulted in an increase of dopamine levels in the presynaptic compartment of nigrostriatal dopamine neurons, hypodopaminergia in the prefrontal cortex (PFC) and schizophrenia-like behavioural deficits in the mouse. RNA sequencing from the PFC revealed gene expression changes similar to those previously found in schizophrenia patients, including downregulation of dopamine receptor 2 and adenosine A2a receptor (A2AR). Treatment of mice with A2AR antagonist istradefylline partially restored striatal and cortical dopamine levels, suggesting a potential therapeutic strategy to alleviate symptoms associated with schizophrenia. Taken together, our results demonstrate that timed increase in GDNF expression is sufficient to drive schizophrenia-like molecular and behavioural phenotypes, and represents a novel model for studying schizophrenia-associated pathologies in mice.
2023-01-03 | GSE162974 | GEO
Project description:Background Chromosome 16p11.2 is one of the most significant loci in the genome-wide association study (GWAS) of schizophrenia. Despite several integrative analyses and functional genomics studies have been carried out to identify possible risk genes, their impacts in the pathogenesis of schizophrenia remain to be fully characterized. Methods We performed expression quantitative trait loci (eQTL) and summary-data-based Mendelian randomization (SMR) analyses to identify schizophrenia risk genes in the 16p11.2 GWAS locus. We constructed the murine model with dysregulated expression of risk gene in the medial prefrontal cortex (mPFC) using stereotaxic injection of Adeno-associated Virus (AAV), followed by behavioral assessments, dendritic spine analyses and RNA sequencing. Findings We identified significant associations between elevated INO80E mRNA expression in frontal cortex and risk of schizophrenia. The mice overexpressing Ino80e in mPFC (Ino80e-OE) exhibited schizophrenia-like behaviors, including increased anxiety behavior, anhedonia, and impaired prepulse inhibition (PPI) when compared with control group. The neuronal sparse labeling assay showed that the density of mushroom spines in the pyramidal neurons of mPFC was significantly decreased in Ino80e-OE mice compared with control mice, accompanied by a notable increase in the density of stubby spines. Transcriptomic analysis in the mPFC revealed significant alterations in the mRNA levels of schizophrenia-related genes and processes related to synapses upon overexpressing Ino80e . Interpretation Our results suggest that upregulation of the Ino80e gene in mPFC may induce schizophrenia-like behaviors in mice, further supporting the hypothesis that INO80E is an authentic risk gene.
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Project description:Treatment of oocytes derived from large (4-6 mm; LG) or small (>3 mm; SM) follicles with glial cell line-derived neurotrophic factor (GDNF) during in vitro maturation. Four-condition experiment, SM and LG oocytes, each with and without GDNF. Biological replicates: 9 per condition, independently collected. Pools of three replicates per array.
2012-11-09 | E-GEOD-42198 | biostudies-arrayexpress
Project description:Treatment of oocytes derived from large (4-6 mm; LG) or small (>3 mm; SM) follicles with glial cell line-derived neurotrophic factor (GDNF) during in vitro maturation.
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Project description:GDNF-regulated gene expression was studied in cultures of actively self-renewing spermatogonial stem cells established from 6 day old male mice. GDNF is the essential growth factor regulating mouse spermatogonial stem cell self-renewal. Using a serum-free chemically defined culture system that supports mouse spermatogonial stem cell self-renewal for extended periods of time, GDNF-regulated genes were identified using microarray profiling. Keywords: GDNF withdrawal and time-course replacement
2006-05-11 | GSE4799 | GEO
Project description:Expression of GDNF-regulated genes was studied in cultures of self-renewing rat spermatogonial stem cells established from 8-10 day old rat pups maintained in a defined serum free medium. GDNF is the primary regulator of spermatogonial stem cell self renewal in the rat. GDNF regulated genes were identified using microarray profiling rat spermatogonial stem cells in the presence and absence of GDNF.
2009-04-14 | GSE15652 | GEO
Project description:Glioblastoma (GBM) is the most common primary brain tumor in adults, characterized by an inherent aggressivity and resistance to treatment leading to poor prognoses. While some resistance mechanisms have been elucidated, a deeper understanding of these mechanisms is needed to increase therapeutic efficacy. In this study we first discovered glial-cell derived neurotrophic factor (GDNF) to be upregulated in patient-derived glioblastoma spheroid cultures after chemotherapeutic temozolomide (TMZ) treatment, through RNA-Seq experiments. Therefore, we investigated the role of the GDNF/GDNF receptor alpha 1 (GFRA1) signaling pathway as a resistance mechanism to chemotherapy with temozolomide and lomustine as well as irradiation using patient-derived glioblastoma spheroid cultures. With qPCR experiments we showed a consistent upregulation of GDNF and its primary receptor GFRA1 following all three lines of treatment. Moreover, CRISPR/Cas9 knock-outs of GDNF in two patient-derived models sensitized these cells to chemotherapy treatment, but not radiotherapy. The increased sensitivity was completely reversed by the addition of exogeneous GDNF, confirming the key role of this factor in chemoresistance. Finally, a CRISPR KO of GFRA1 demonstrated a similar increased sensitivity to temozolomide and lomustine treatment, as well as radiotherapy. Together, our findings support the role of the GDNF/GFRA1 signaling pathway in glioblastoma chemo and radioresistance.
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Project description:We report a significant change in epithelial differentiation pathways and principal cell specific transcription factors in tubuloids with a GDNF pulse, when compared to control tubuloid cultures.
2020-06-08 | GSE151949 | GEO
Project description:GDNF-regulated gene expression was studied in cultures of actively self-renewing spermatogonial stem cells established from 6 day old male mice. GDNF is the essential growth factor regulating mouse spermatogonial stem cell self-renewal. Using a serum-free chemically defined culture system that supports mouse spermatogonial stem cell self-renewal for extended periods of time, GDNF-regulated genes were identified using microarray profiling. Experiment Overall Design: Established cultures of highly enriched self-renewing spermatogonial stem cells were subjeted to withrawal of GDNF and GFRalpha1 for 18-hr followed by replacement of the growth factors for 2, 4, and 8-hr. Gene expression was studied using microarray profiling prior to withdrawal, after withdrawal and at each time-point of GDNF/GFRalpha1 replacement.
2007-11-24 | E-GEOD-4799 | biostudies-arrayexpress
Project description:Expression of GDNF-regulated genes was studied in cultures of self-renewing rat spermatogonial stem cells established from 8-10 day old rat pups maintained in a defined serum free medium. GDNF is the primary regulator of spermatogonial stem cell self renewal in the rat. GDNF regulated genes were identified using microarray profiling rat spermatogonial stem cells in the presence and absence of GDNF. Experiment Overall Design: Highly enriched population of rat spermatogonial stem cells were maintained in defined serum free media which allowed for their continued self-renewal in the presence of GDNF. GDNF was withdrawn from cultures for 18 hours followed by replacement for 2, 4, and 8 hours. Gene expression was studied using microarray profiling prior to GDNF withdrawal, after GDNF withdrawal, and after 2, 4, and 8 hours of GDNF replacement. 3 replicate samples from each timepoint were analyzed.
2009-04-18 | E-GEOD-15652 | biostudies-arrayexpress