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Rupert W Overall

Rupert W Overall

PhD

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74
Publications
10,069
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1,667
Citations

Publications

Publications (74)
Article
Full-text available
Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify gen...
Article
Although the neurogenesis-enhancing effects of exercise have been extensively studied, the molecular mechanisms underlying this response remain unclear. Here, we propose that this is mediated by the exercise-induced systemic release of the antioxidant selenium transport protein, selenoprotein P (SEPP1). Using knockout mouse models, we confirmed tha...
Article
Full-text available
We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 mole...
Article
Full-text available
Adult neurogenesis enables the life-long addition of functional neurons to the hippocampus and is regulated by both cell-intrinsic molecular programs and behavioral activity. De novo DNA methylation is crucial for embryonic brain development, but its role during adult hippocampal neurogenesis has remained unknown. Here, we show that de novo DNA met...
Article
Full-text available
The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment count...
Preprint
Full-text available
Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetic methods to quantify gene...
Article
Full-text available
As mammals evolved with exposure to particular diets, naturally abundant compounds may have become part of the set of environmental co-determinants that shaped brain structure and function. Here we investigated whether bioactive factors found in apples directly affect hippocampal neurogenesis in the adult mouse. We found that quercetin, the most ab...
Article
Full-text available
Cellular redox states regulate the balance between stem cell maintenance and activation. Increased levels of intracellular reactive oxygen species (ROS) are linked to proliferation and lineage specification. In contrast to this general principle, we here show that in the hippocampus of adult mice, quiescent neural precursor cells (NPCs) maintain th...
Preprint
Full-text available
Dynamic DNA methylation controls gene-regulatory networks underlying cell fate specification. How DNA methylation patterns change during adult hippocampal neurogenesis and their relevance for adult neural stem cell differentiation and related brain function has, however, remained unknown. Here, we show that neurogenesis-associated de novo DNA methy...
Article
Full-text available
Individuals differ in their response to environmental stimuli, but the stability of individualized behaviors and their associated changes in brain plasticity are poorly understood. We developed a novel model of enriched environment to longitudinally monitor 40 inbred mice exploring 35 connected cages over periods of 3 to 6 months. We show that beha...
Article
Altered neural stem/progenitor cell (NSPC) activity and neurodevelopmental defects are linked to intellectual disability. However, it remains unclear whether altered metabolism, a key regulator of NSPC activity, disrupts human neurogenesis and potentially contributes to cognitive defects. We investigated links between lipid metabolism and cognitive...
Preprint
Full-text available
As mammals evolved exposed to particular diets, naturally abundant compounds may have become part of the set of environmental co-determinants that shaped brain structure and function. Here we investigated whether bioactive factors found in apples directly affect hippocampal neural stem cells and promote neurogenesis in the adult mouse. Whereas the...
Preprint
Full-text available
Rtrack is an open-source software package for the analysis of spatial exploration data from behavioural tests such as the Morris water maze. The software provides an easy-to- use interface for data import, analysis and visualisation. A parameter-free machine learning model allows rapid and reproducible classification of spatial search strategies. W...
Preprint
Full-text available
Individuals differ in their response to environmental stimuli, but the stability of individualized behaviors and their associated changes in brain plasticity are poorly understood. We developed a novel model of enriched environment to longitudinally monitor 40 inbred mice exploring 35 connected cages over periods of three to six months. We show tha...
Preprint
Full-text available
The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that environmental enrichment counteracted age-rela...
Article
Full-text available
Physical exercise has well-established anti-inflammatory effects, with neuro-immunological crosstalk being proposed as a mechanism underlying the beneficial effects of exercise on brain health. Here, we used physical exercise, a strong positive modulator of adult hippocampal neurogenesis, as a model to identify immune molecules that are secreted in...
Preprint
Full-text available
Intracellular redox states regulate the balance between stem cell maintenance and activation. Increased levels of reactive oxygen species (ROS) are linked to proliferation and lineage specification. In contrast to this general principle, we show that in the hippocampus of adult mice it is the quiescent neural stem cells (NSCs) that maintain the hig...
Data
Document S1. Supplemental Experimental Procedures, Figures S1 and S2, and Tables S1–S11
Article
Full-text available
Physical activity is a strong positive physiological modulator of adult neurogenesis in the hippocampal dentate gyrus. Although the underlying regulatory mechanisms are still unknown, systemic processes must be involved. Here we show that platelets are activated after acute periods of running, and that activated platelets promote neurogenesis, an e...
Article
Full-text available
Making mechanistic sense of genetically complex biological systems such as adult hippocampal neurogenesis poses conceptual and many practical challenges. Transcriptomics studies have helped to move beyond single-gene approaches and have greatly enhanced the accessibility to effects of greater numbers of genes. Typically, however, the number of expe...
Chapter
Phenotypes collected with a view to quantitative trait locus mapping can be augmented with compatible whole-transcriptome expression data and information from several other sources. These different data sources can be assembled into multidimensional network models which allow the identification of key genes potentially driving the phenotype of inte...
Article
Full-text available
The number of proliferating neural precursor cells in the adult hippocampus is strongly increased by physical activity. The mechanisms through which this behavioral stimulus induces cell proliferation, however, are not yet understood. In fact, even the mode of proliferation of the stem and progenitor cells is not exactly known. Evidence exists for...
Article
Full-text available
An individual’s genetic makeup plays an important role in determining susceptibility to cognitive aging. Identifying the specific genes that contribute to cognitive aging may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specifi...
Data
Table S3. Quantitative Gene Expression Analysis Data of Single Organoids throughout Retinal Organoidogenesis, Related to Figure 4
Data
Document S1. Supplemental Experimental Procedures, Figures S1–S7, and Tables S1 and S2
Data
Document S1. Supplemental Experimental Procedures, Figures S1–S5, and Tables S3 and S4
Article
Full-text available
The plasticity of pluripotent stem cells provides new possibilities for studying development, degeneration, and regeneration. Protocols for the differentiation of retinal organoids from embryonic stem cells have been developed, which either recapitulate complete eyecup morphogenesis or maximize photoreceptor genesis. Here, we have developed a proto...
Article
Full-text available
Here, we show that the lysophosphatidic acid receptor 1 (LPA1) is expressed by a defined population of type 1 stem cells and type 2a precursor cells in the adult mouse dentate gyrus. LPA1, in contrast to Nestin, also marks the quiescent stem cell population. Combining LPA1-GFP with EGFR and prominin-1 expression, we have enabled the prospective sep...
Article
In much animal research, genetic variation is rather avoided than utilized as a powerful tool to identify key regulatory genes in complex phenotypes. Adult hippocampal neurogenesis is one such highly complex polygenic trait, for which the understanding of the molecular basis is fragmented and incomplete, and for which novel genetic approaches are n...
Article
Full-text available
Adult neurogenesis, the lifelong production of new neurons in the adult brain, is under complex genetic control but many of the genes involved remain to be identified. In this study, we have integrated publicly available gene expression data from the BXD and CXB recombinant inbred mouse lines to discover genes co-expressed in the adult hippocampus...
Article
Full-text available
Exercise stimulates cellular brain plasticity by extending the pool of proliferating neural precursor cells in the adult hippocampus. This effect has been investigated extensively, but the most immediate cellular effect induced by exercise that results in this acute increase in the number of cycling cells remained unclear. In the developing brain a...
Article
Full-text available
This study builds on the findings that physical activity, such as wheel running in mice, enhances cell proliferation and neurogenesis in the adult hippocampus of the common mouse strain C57BL/6, and that the baseline level of neurogenesis varies by strain, being considerably lower in DBA/2. Because C57BL/6 and DBA/2 are important as the parental st...
Article
Full-text available
Adult hippocampal neurogenesis is to a large degree controlled at the level of cell survival, and a number of potential mediators of this effect have been postulated. Here, we investigated the small heat shock protein Hspb8, which, because of its pleiotropic prosurvival effects in other systems, was considered a particularly promising candidate fac...
Article
Full-text available
The gene WFS1 encodes a protein with unknown function although its functional deficiency causes different neuropsychiatric and neuroendocrine syndromes. In the present study, we aimed to find the functional networks influenced by the time-dependent silencing of WFS1 in HEK cells. We performed whole genome gene expression profiling (Human Gene 1.0 S...
Article
Full-text available
Adult hippocampal neurogenesis is not a single phenotype, but consists of a number of sub-processes, each of which is under complex genetic control. Interpretation of gene expression studies using existing resources often does not lead to results that address the interrelatedness of these processes. Formal structure, such as provided by ontologies,...
Data
The complete MANGO database. Each row of the table contains all reported effects of a single gene in a single manuscript. Genes annoated to the MANGO database are listed as official MGI mouse gene symbol, official gene name and common names, and NCBI GeneID. Abbreviations for cell types/markers are: Ast, astrocytes; BrdU, cells positive after label...
Data
Genes used for enrichment analysis. Gene lists were obtained by correlating data for two adult hippocampal neurogenesis phenotypes with brain transcript expression values measured in the same strains of a genetic reference population. For more details on this experiment please refer to the original publication [18]. Raw data are available at GeneNe...
Article
Full-text available
In the search for ways to combat degenerative neurological disorders, neurogenesis-stimulating factors are proving to be a promising area of research. In this study, we show that the hormonal factor prolactin (PRL) can activate a pool of latent precursor cells in the adult mouse hippocampus. Using an in vitro neurosphere assay, we found that the ad...
Article
Durable osseointegration of metallic bone implants requires that progenitor cells attach, proliferate and differentiate on the implant surface. Previously, we demonstrated superior biocompatibility of human mesenchymal stromal cells (MSCs) cultivated on ultrasmooth tantalum (Ta) as compared to titanium (Ti) surface. The aim of this study was to ext...
Article
Full-text available
BESIDES THE MASSIVE PLASTICITY AT THE LEVEL OF SYNAPSES, WE FIND IN THE HIPPOCAMPUS OF ADULT MICE AND RATS TWO SYSTEMS WITH VERY STRONG MACROSCOPIC STRUCTURAL PLASTICITY: adult neurogenesis, that is the lifelong generation of new granule cells, and dynamic changes in the mossy fibers linking the dentate gyrus to area CA3. In particular the anatomy...
Article
Full-text available
The hippocampus of adult rodents harbors two systems exhibiting structural plasticity beyond the level of synapses and dendrites. First, the persistent generation of granule cells (adult neurogenesis); second, dynamic changes in the mossy fibers (MF), in particular in the infrapyramidal mossy fiber (IMF) tract. Because MFs are the axons of granule...
Data
Regulators (quantitative trait genes) for Qrr1 as suggested by MDP mapping data. (0.05 MB DOC)
Data
Full-text available
Correlation between the strength of MDP eQTL scores and their ability to correctly map causal genes. The eQTL intervals are ordered according to decreasing MDP eQTL scores, e.g. longer lists include lower scores. (0.00 MB PDF)
Data
Full-text available
MDP-based candidate gene selection at different ΔcM. (0.13 MB PDF)
Data
Full-text available
Enrichment of Usf1 targets along Qrr1 at different thresholds in the BXD and MDP datasets, and different p-value cutoffs for defining targets from the over-expression experiment. A: lower p-value cutoff (0.1, 5839 targets); B: higher p-value cutoff (0.01, 850 targets); C: lower BXD threshold (99.5% percentile, 285 genes selected); D: higher MDP thr...
Data
Full-text available
Functional enrichment of target genes linking to Qrr1. The average MDP eQTL score at each marker in Qrr1 is reported for all genes of a specific class. (0.84 MB PDF)
Data
Functional enrichment analysis of genes that map to Qrr1 in the BXD hippocampus data set. (0.02 MB XLS)
Data
Full-text available
Assessment of MDP-based candidate gene selection - trans-eQTL only. For each of the selected loci a selected candidate gene was considered as a true positive if it is part of a common pathway with the target gene. The figure shows the fraction of loci with correct selections; x-axis shows inclusion of successively more eQTL intervals at decreasing...
Article
Full-text available
The study of expression quantitative trait loci (eQTL) is a powerful way of detecting transcriptional regulators at a genomic scale and for elucidating how natural genetic variation impacts gene expression. Power and genetic resolution are heavily affected by the study population: whereas recombinant inbred (RI) strains yield greater statistical po...
Conference Paper
The subgranular zone of the dentate gyrus of sexually mature mice contains a highly variable number of pluripotent stem cells that produce a stream of intermediate progenitors which give rise to neurons and glial cells. Genetic factors, age, and the environment control variation in the fate and rate of neurogenesis. Discovery of stem cells in the a...
Article
Full-text available
Differences in gene expression in the CNS influence behavior and disease susceptibility. To systematically explore the role of normal variation in expression on hippocampal structure and function, we generated an online microarray database for a diverse panel of strains of mice, including most common inbred strains and numerous recombinant inbred l...
Article
Full-text available
Author Summary Neural stem cells divide and generate new neurons throughout life in the mammalian hippocampus. After a distinct maturation process, newborn neurons become functionally integrated into the preexisting circuitry and appear to participate in hippocampal function, which is critically involved in certain forms of learning and memory. Ho...
Data