Developmental, cellular, and behavioral phenotypes in a mouse model of congenital hypoplasia of the dentate gyrus
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE157983 | GEO | 2020/10/01
REPOSITORIES: GEO
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Project description:In the hippocampus, a widely accepted model posits that the dentate gyrus improves learning and memory by enhancing discrimination between inputs. To test this model, we studied conditional knockout mice in which the vast majority of dentate granule cells (DGCs) fail to develop - including nearly all DGCs in the dorsal hippocampus - secondary to eliminating Wntless (Wls) in a subset of cortical progenitors with Gfap-Cre. Other cells in the Wlsfl/-;Gfap-Cre hippocampus were minimally affected, as determined by single nucleus RNA sequencing. CA3 pyramidal cells, the targets of DGC-derived mossy fibers, exhibited normal morphologies with a small reduction in the numbers of synaptic spines. Wlsfl/-;Gfap-Cre mice have a modest performance decrement in several complex spatial tasks, including active place avoidance. They were also modestly impaired in one simpler spatial task, finding a visible platform in the Morris water maze. These experiments support a role for DGCs in enhancing spatial learning and memory.
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Project description:Developmental, cellular, and behavioral phenotypes in a mouse model of congenital hypoplasia of the dentate gyrus
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Project description:Fear learning is highly adaptive if utilized in appropriate situations but can lead to generalized anxiety if applied too widely. A role of predictive cues in inhibiting fear generalization has been suggested by stress and fear learning studies, but the effects of partially predictive cues (ambiguous cues) and the neuronal populations responsible for linking the predictive ability of cues and generalization of fear responses are unknown. Here, we show that inhibition of adult neurogenesis in the mouse dentate gyrus decreases hippocampal network activation and reduces defensive behavior to ambiguous threat cues but has neither of these effects if the same negative experience is reliably predicted. Additionally, we find that this ambiguity related to negative events determines their effect on fear generalization, that is, how the events affect future behavior under novel conditions. Both new neurons and glucocorticoid hormones are required for the enhancement of fear generalization following an unpredictably cued threat. Thus, adult neurogenesis plays a central role in the adaptive changes resulting from experience involving unpredictable or ambiguous threat cues, optimizing behavior in novel and uncertain situations.
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Project description:Oxaliplatin is a commonly used chemotherapeutic drug for the treatment of pancreatic cancer. Understanding the cellular mechanisms of oxaliplatin resistance is important for developing new strategies to overcome drug resistance in pancreatic cancer. In this study, we performed a stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics analysis of oxaliplatin-resistant and sensitive pancreatic cancer PANC-1 cells. We identified 107 proteins whose expression levels changed between oxaliplatin-resistant and sensitive cells, which were involved in multiple biological processes, including DNA repair, drug response, apoptotic signalling, and the type 1 interferon signalling pathway. Notably, myristoylated alanine-rich C-kinase substrate (MARCKS) and wntless homolog protein (WLS) were upregulated in oxaliplatin-resistant cells compared to sensitive cells, as confirmed by qRT-PCR and Western blot analysis. We further demonstrated the activation of AKT and β-catenin signalling (downstream targets of MARCKS and WLS, respectively) in oxaliplatin-resistant PANC-1 cells. Additionally, we show that the siRNA-mediated suppression of both MARCKS and WLS enhanced oxaliplatin sensitivity in oxaliplatin-resistant PANC-1 cells. Taken together, our results provide insights into multiple mechanisms of oxaliplatin resistance in pancreatic cancer cells and reveal that MARCKS and WLS might be involved in the chemotherapeutic resistance in pancreatic cancer.
2021-09-09 | PXD021251 | Pride
Project description:The purpose of this study was to identify the source of Wnt signals that lead to development/proliferation of the heart fields, particularly the second heart field. To this end, we knocked out Wntless (Wls), which is necessary for Wnt secretion, in Mesp1+ lineage cells. We performed single cell RNA-seq to better identify the source of Wnt signals and the effects of the loss of Wnt secretion in mesoderm.
2021-01-23 | GSE165300 | GEO
Project description:Immature dentate granule cells (DGCs) generated in the hippocampus during adulthood are believed to play a unique role in dentate gyrus function. Although immature DGCs have hyperexcitable membrane properties in vitro, the consequences of this hyperexcitability in vivo remain unclear. In particular, the relationship between experiences that activate the dentate gyrus, such as exploration of a novel environment (NE), and downstream molecular processes that modify dentate gyrus circuitry in response to cellular activation are unknown in this cell population. We first performed quantification of immediate early gene proteins in immature (5-week-old) and mature (13-week-old) DGCs from mice exposed to a NE. Paradoxically, we observed lower immediate early gene protein expression in hyperexcitable immature DGCs. We then isolated nuclei from active and inactive immature DGCs and performed single nuclei RNA-Sequencing. Compared to mature nuclei collected from the same animal, immature DGC nuclei showed less activity-induced transcriptional change, even though they were classified as active based on expression of ARC protein. These results demonstrate that the coupling of spatial exploration, cellular activation, and transcriptional change differs between immature and mature DGCs, with blunted activity-induced changes in immature cells.
2023-02-23 | GSE214309 | GEO
Project description:[This corrects the article DOI: 10.1371/journal.pbio.2001154.].
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Project description:Wnt signaling in early eye development, specifically the lens placode shows expression of 12 out of 19 Wnt ligands. We these Wnt activities were suppressed using conditional deletion of Wntless, dramatic phenotypic changes in morphogensis occurred. Microarray analysis of the genes that were changed in response to deletion of Wnt ligands in the developing eye region show direct or indirect responses from the surface ectoderm to the developing RPE and optic cup curvature, creating an overal shape change phenotype in the bilayerd epithelium of the optic cup. Mouse embryos at embryonic stage e10.5 were disected into pbs and eye regions were disected and removed for RNA extraction and hybridization to Affymetrix microarrays. We sought to identify the genes that were changed in response to deletion of Wls from the developing surface ectoderm of the eye region. Genes changed could be the direct or indirect result from deleltion of Wls from the surface ectoderm using the LeCre recombinase gene as a tool for analysis.
2015-01-22 | E-GEOD-65154 | biostudies-arrayexpress
Project description:Neurons are born and become a functional part of the synaptic circuitry in adult brains. The proliferative phase of neurogenesis has been extensively reviewed. We therefore focus this review on a few topics addressing the functional role of adult-generated newborn neurons in the dentate gyrus. We discuss the evidence for a link between neurogenesis and behavior. We then describe the steps in the integration of newborn neurons into a functioning mature synaptic circuit. Given the profound effects of neural activity on the differentiation and integration of newborn neurons, we discuss the role of activity-dependent gene expression in the birth and maturation of newborn neurons. The differentiation and maturation of newborn neurons likely involves the concerted action of many genes. Thus we focus on transcription factors that can direct large changes to the transcriptome, and microRNAs, a newly-discovered class of molecules that can effect the expression of hundreds of genes. How microRNAs affect the generation and integration of newborn neurons is just being explored, but there are compelling clues hinting at their involvement.
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Project description:BackgroundSchizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined.MethodsHippocampal formation (HF) subregion volumes were obtained using FreeSurfer 6.0 from individuals with schizophrenia (n = 176, mean age ± s.d. = 39.0 ± 11.5, 132 males) and healthy volunteers (n = 173, mean age ± s.d. = 37.6 ± 11.3, 123 males) with similar mean age, gender, handedness, and race distributions. Relationships between the HF subregion volume with the largest between group difference, neuropsychological performance, and single-nucleotide polymorphisms were assessed.ResultsThis study found a significant group by region interaction on hippocampal subregion volumes. Compared to healthy volunteers, individuals with schizophrenia had significantly smaller dentate gyrus (DG) (Cohen's d = -0.57), Cornu Ammonis (CA) 4, molecular layer of the hippocampus, hippocampal tail, and CA 1 volumes, when statistically controlling for intracranial volume; DG (d = -0.43) and CA 4 volumes remained significantly smaller when statistically controlling for mean hippocampal volume. DG volume showed the largest between group difference and significant positive associations with visual memory and speed of processing in the overall sample. Genome-wide association analysis with DG volume as the quantitative phenotype identified rs56055643 (β = 10.8, p < 5 × 10-8, 95% CI 7.0-14.5) on chromosome 3 in high linkage disequilibrium with MOBP. Gene-based analyses identified associations between SLC25A38 and RPSA and DG volume.ConclusionsThis study suggests that DG dysfunction is fundamentally involved in schizophrenia pathophysiology, that it may contribute to cognitive abnormalities in schizophrenia, and that underlying biological mechanisms may involve contributions from MOBP, SLC25A38, and RPSA.
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