scholarly journals Functional Mature Human Microglia Developed in Human iPSC Microglial Chimeric Mouse Brain

2019 ◽  
Author(s):  
Ranjie Xu ◽  
Andrew J. Boreland ◽  
Xiaoxi Li ◽  
Anthony Posyton ◽  
Kelvin Kwan ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Disease Risk ◽  
Expression Patterns ◽  
Chimeric Mouse ◽  
Post Transplantation ◽  
Human Microglia ◽  
Species Specific ◽  
Human Ipsc ◽  
The Brain

AbstractMicroglia, the brain-resident macrophages, exhibit highly dynamic functions in neurodevelopment and neurodegeneration. Human microglia possess unique features as compared to mouse microglia, but our understanding of human microglial functions is largely limited by an inability to obtain human microglia under homeostatic states. We developed a human pluripotent stem cell (hPSC)-based microglial chimeric mouse brain model by transplanting hPSC-derived primitive macrophage precursors into neonatal mouse brains. The engrafted human microglia widely disperse in the brain and replace mouse microglia in corpus callosum at 6 months post-transplantation. Single-cell RNA-sequencing of the microglial chimeric mouse brains reveals that xenografted hPSC-derived microglia largely retain human microglial identity, as they exhibit signature gene expression patterns consistent with physiological human microglia and recapitulate heterogeneity of adult human microglia. Importantly, the engrafted hPSC-derived microglia exhibit dynamic response to cuprizone-induced demyelination and species-specific transcriptomic differences in the expression of neurological disease-risk genes in microglia. This model will serve as a novel tool to study the role of human microglia in brain development and degeneration.

scholarly journals Genetic Variants of Lipoprotein Lipase and Regulatory Factors Associated with Alzheimer’s Disease Risk

2020 ◽  
Vol 21 (21) ◽  
pp. 8338
Author(s):  
Kimberley D. Bruce ◽  
Maoping Tang ◽  
Philip Reigan ◽  
Robert H. Eckel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipoprotein Lipase ◽  
Genetic Variants ◽  
Disease Risk ◽  
Lipoprotein Metabolism ◽  
Protective Role ◽  
Direct Role ◽  
The Brain

Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the provision of FFAs to metabolic tissues. However, LPL may also contribute to lipoprotein uptake by acting as a molecular bridge between lipoproteins and cell surface receptors. Recent studies have shown that LPL is abundantly expressed in the brain and predominantly expressed in the macrophages and microglia of the human and murine brain. Moreover, recent findings suggest that LPL plays a direct role in microglial function, metabolism, and phagocytosis of extracellular factors such as amyloid- beta (Aβ). Although the precise function of LPL in the brain remains to be determined, several studies have implicated LPL variants in Alzheimer’s disease (AD) risk. For example, while mutations shown to have a deleterious effect on LPL function and expression (e.g., N291S, HindIII, and PvuII) have been associated with increased AD risk, a mutation associated with increased bridging function (S447X) may be protective against AD. Recent studies have also shown that genetic variants in endogenous LPL activators (ApoC-II) and inhibitors (ApoC-III) can increase and decrease AD risk, respectively, consistent with the notion that LPL may play a protective role in AD pathogenesis. Here, we review recent advances in our understanding of LPL structure and function, which largely point to a protective role of functional LPL in AD neuropathogenesis.

scholarly journals Differential Expression of the Carbonic Anhydrase Genes for CA VII (Car7) And CA-RP VIII (Car8) in Mouse Brain

1997 ◽  
Vol 45 (5) ◽  
pp. 657-662 ◽  
Author(s):  
Maha M. Lakkis ◽  
K. Sue O'Shea ◽  
Richard E. Tashian
Keyword(s):  
Carbonic Anhydrase ◽  
Mouse Brain ◽  
Expression Patterns ◽  
Granular Cell ◽  
Cortical Layer ◽  
Cell Layers ◽  
High Level ◽  
The Brain ◽  
Lower Expression

The spatial expression patterns of the two α-carbonic anhydrase genes, CA VII and CA-RP VIII (called Car7 and Car8 in the mouse) were examined in the mouse brain by in situ hybridization. These two genes are the most highly conserved evolutionarily among the mammalian α-CAs. Both genes showed a similarly wide expression pattern in the brain. In the cerebrum, mRNA expression was detected in the pia, choroid plexus, and neurons of the cortical layer, thalamus, and medial habenulae. A high level of expression appeared in the pyramidal and granular cells of the hippocampus. In the cerebellum, both Car7 and Car8 were transcribed to different degrees in the Purkinje cells, and a lower expression level occured in the molecular and granular cell layers. Transcription signals for both genes were excluded from the white matter regions.

scholarly journals Transcriptomic Analysis of the Effects of Chemokine Receptor CXCR3 Deficiency on Immune Responses in the Mouse Brain during Toxoplasma gondii Infection

2021 ◽  
Vol 9 (11) ◽  
pp. 2340
Author(s):  
Kousuke Umeda ◽  
Youta Goto ◽  
Kenichi Watanabe ◽  
Nanako Ushio ◽  
Ragab M. Fereig ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Mouse Brain ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Expression Patterns ◽  
Parasite Burden ◽  
Cxc Chemokine ◽  
Immune Related Genes ◽  
The Brain

The obligate intracellular parasite Toxoplasma gondii infects warm-blooded animals, including humans. We previously revealed through a whole-brain transcriptome analysis that infection with T. gondii in mice causes immune response-associated genes to be upregulated, for instance, chemokines and chemokine receptors such as CXC chemokine receptor 3 (CXCR3) and its ligand CXC chemokine ligand 10 (CXCL10). Here, we describe the effect of CXCR3 on responses against T. gondii infection in the mouse brain. In vivo assays using CXCR3-deficient mice showed that the absence of CXCR3 delayed the normal recovery of body weight and increased the brain parasite burden, suggesting that CXCR3 plays a role in the control of pathology in the brain, the site where chronic infection occurs. Therefore, to further analyze the function of CXCR3 in the brain, we profiled the gene expression patterns of primary astrocytes and microglia by RNA sequencing and subsequent analyses. CXCR3 deficiency impaired the normal upregulation of immune-related genes during T. gondii infection, in astrocytes and microglia alike. Collectively, our results suggest that the immune-related genes upregulated by CXCR3 perform a particular role in controlling pathology when the host is chronically infected with T. gondii in the brain.

An Explanation for How FGFs Predict Species-Specific Tooth Cusp Patterns

2018 ◽  
Vol 97 (7) ◽  
pp. 828-834 ◽  
Author(s):  
L. Li ◽  
Q. Tang ◽  
H.-J.E. Kwon ◽  
Z. Wu ◽  
E.-J. Kim ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Expression Patterns ◽  
Evolutionary Changes ◽  
The Future ◽  
Predictive Role ◽  
Species Specific ◽  
Enamel Knots ◽  
Inner Dental Epithelium

Species-specific cusp patterns result from the iterative formation of enamel knots, the epithelial signaling centers, at the future cusp positions. The expressions of fibroblast growth factors (FGFs), especially Fgf4, in the secondary enamel knots in the areas of the future cusp tips are generally used to manifest the appearance of species-specific tooth shapes. However, the mechanism underlying the predictive role of FGFs in species-specific cusp patterns remains obscure. Here, we demonstrated that gerbils, which have a lophodont pattern, exhibit a striped expression pattern of Fgf4, whereas mice, which have a bunodont pattern, have a spotted expression pattern, and these observations verify the predictive role of Fgf4 in species-specific cusp patterns. By manipulating FGFs’ signaling in the inner dental epithelium of gerbils, we provide evidence for the intracellular participation of FGF signaling, specifically FGF4 and FGF20, in Rac1- and RhoA-regulated cellular geometry remolding during the determination of different cusp patterns. Our study presents a novel explanation of how different FGF expression patterns produce different cusp patterns and implies that a conserved intracellular FGF-GTPase signaling module might represent an underlying developmental basis for evolutionary changes in cusp patterns.

scholarly journals Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ranjie Xu ◽  
Xiaoxi Li ◽  
Andrew J. Boreland ◽  
Anthony Posyton ◽  
Kelvin Kwan ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Chimeric Mouse ◽  
Human Ipsc

scholarly journals Granulins Regulate Aging Kinetics in the Adult Zebrafish Telencephalon

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 350 ◽  
Author(s):  
Alessandro Zambusi ◽  
Özge Pelin Burhan ◽  
Rossella Di Giaimo ◽  
Bettina Schmid ◽  
Jovica Ninkovic
Keyword(s):  
Premature Aging ◽  
Therapeutic Approaches ◽  
Human Microglia ◽  
Transcriptional Signature ◽  
New Therapeutic Approaches ◽  
Inflammatory Phenotype ◽  
Transcriptional Changes ◽  
Aging Kinetics ◽  
The Brain

Granulins (GRN) are secreted factors that promote neuronal survival and regulate inflammation in various pathological conditions. However, their roles in physiological conditions in the brain remain poorly understood. To address this knowledge gap, we analysed the telencephalon in Grn-deficient zebrafish and identified morphological and transcriptional changes in microglial cells, indicative of a pro-inflammatory phenotype in the absence of any insult. Unexpectedly, activated mutant microglia shared part of their transcriptional signature with aged human microglia. Furthermore, transcriptome profiles of the entire telencephali isolated from young Grn-deficient animals showed remarkable similarities with the profiles of the telencephali isolated from aged wildtype animals. Additionally, 50% of differentially regulated genes during aging were regulated in the telencephalon of young Grn-deficient animals compared to their wildtype littermates. Importantly, the telencephalon transcriptome in young Grn-deficent animals changed only mildly with aging, further suggesting premature aging of Grn-deficient brain. Indeed, Grn loss led to decreased neurogenesis and oligodendrogenesis, and to shortening of telomeres at young ages, to an extent comparable to that observed during aging. Altogether, our data demonstrate a role of Grn in regulating aging kinetics in the zebrafish telencephalon, thus providing a valuable tool for the development of new therapeutic approaches to treat age-associated pathologies.

scholarly journals A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia

2019 ◽  
Author(s):  
Thomas M Piers ◽  
Katharina Cosker ◽  
Anna Mallach ◽  
Gabriel Thomas Johnson ◽  
Rita Guerreiro ◽  
...  
Keyword(s):  
Immune Cell ◽  
Loss Of Function ◽  
Human Patient ◽  
Metabolic Switch ◽  
Risk Variant ◽  
Β Amyloid ◽  
Human Ipsc ◽  
Plastic Responses ◽  
The Brain

AbstractLoss-of-function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2 and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on microglial metabolic function in human patient iPSC-derived-microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimer’s disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signalling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD.

scholarly journals Appetite regulating genes in zebrafish gut; a gene expression study

2021 ◽  
Author(s):  
Ehsan Pashay Ahi ◽  
Mathilde Brunel ◽  
Emmanouil Tsakoumis ◽  
Junyu Chen ◽  
Monika Schmitz
Keyword(s):  
Gastrointestinal Tract ◽  
Leptin Receptor ◽  
Expression Patterns ◽  
Differentially Expressed ◽  
Wild Type ◽  
Signal Functions ◽  
Multiple Organs ◽  
Normal Feeding ◽  
The Brain

The underlying molecular pathophysiology of feeding disorders, particularly in peripheral organs, is still largely unknown. A range of molecular factors encoded by appetite-regulating genes are already described to control feeding behaviour in the brain. However, the important role of the gastrointestinal tract in the regulation of appetite and feeding in connection to the brain has gained more attention in the recent years. An example of such inter-organ molecular interaction can be the signals mediated by leptin, a key regulator of body weight, food intake and metabolism, with conserved anorexigenic effects in vertebrates. Leptin signal functions through its receptor ( lepr ) in multiple organs, including the brain and the gastrointestinal tract. So far, the regulatory connections between leptin signal and other appetite-regulating genes remain unclear, particularly in the gastrointestinal system. In this study, we used a zebrafish mutant with impaired function of leptin receptor to explore gut expression patterns of appetite-regulating genes, under different feeding conditions (normal feeding, 7-day fasting, 2 and 6-hours refeeding). We compared these expression patterns to those from wild-type zebrafish, in order to identify leptin-dependent differentially expressed genes located in the zebrafish gut. We provide evidence that most appetite-regulating genes are expressed in the zebrafish gut. On one hand, we did not observed significant differences in the expression of orexigenic genes after changes in the feeding condition, and only one orexigenic gene, hcrt , displayed differential expression under impaired leptin signal. On the other hand, we found 8 anorexigenic genes in wild-types ( cart2 , cart3 , dbi , oxt , nmu , nucb2a , pacap and pomc ), as well as 4 genes in lepr mutants ( cart3 , kiss1, kiss1r and nucb2a ), to be differentially expressed in the zebrafish gut after changes in feeding conditions. Most of these genes also showed significant differences in their expression between wild-type and lepr mutant in at least one of the feeding conditions. Finally, we observed that impaired leptin signalling influences potential regulatory connections between anorexigenic genes in zebrafish gut, particularly connections involving cart2 , cart3 , kiss1 , kiss1r , mchr2 , nmu , nucb2a and oxt . Altogether, these transcriptional changes propose a potential role of the gastrointestinal tract in the regulation of feeding through changes in expression of certain anorexigenic genes in zebrafish.

scholarly journals Sex Determination and Differentiation in Teleost: Roles of Genetics, Environment, and Brain

Biology ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 973
Author(s):  
Preetha Rajendiran ◽  
Faizul Jaafar ◽  
Sonika Kar ◽  
Chenichery Sudhakumari ◽  
Balasubramanian Senthilkumaran ◽  
...  
Keyword(s):  
Environmental Factors ◽  
Sex Determination ◽  
Developmental Process ◽  
Sex Differentiation ◽  
Reproductive Organ ◽  
Cellular Level ◽  
Complex Biological System ◽  
Species Specific ◽  
The Brain

The fish reproductive system is a complex biological system. Nonetheless, reproductive organ development is conserved, which starts with sex determination and then sex differentiation. The sex of a teleost is determined and differentiated from bipotential primordium by genetics, environmental factors, or both. These two processes are species-specific. There are several prominent genes and environmental factors involved during sex determination and differentiation. At the cellular level, most of the sex-determining genes suppress the female pathway. For environmental factors, there are temperature, density, hypoxia, pH, and social interaction. Once the sexual fate is determined, sex differentiation takes over the gonadal developmental process. Environmental factors involve activation and suppression of various male and female pathways depending on the sexual fate. Alongside these factors, the role of the brain during sex determination and differentiation remains elusive. Nonetheless, GnRH III knockout has promoted a male sex-biased population, which shows brain involvement during sex determination. During sex differentiation, LH and FSH might not affect the gonadal differentiation, but are required for regulating sex differentiation. This review discusses the role of prominent genes, environmental factors, and the brain in sex determination and differentiation across a few teleost species.

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