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Project description:Transcriptome analysis of brain endothelial cells from EC-specific Glut1 knock-out mice
| PRJNA595177 | ENA
Project description:To explore the mechanisms through which GLUT1 controls EC function, we compared transcriptomic alterations induced by loss of GLUT1 by performing RNA sequencing analysis on freshly isolated ECs from adult (8 week old) GLUT1EC-/- brains. In adult brains ECs, 1494 genes were differentially expressed between WT and GLUT1-/- ECs but we did not observe compensatory upregulation of other GLUTs. Interestingly, pathway analysis revealed that ECs from GLUT1EC-/- mice were characterized by a robust activation of inflammatory and extracellular matrix pathways.
2020-06-01 | GSE141923 | GEO
Project description:To explore the mechanisms through which GLUT1 controls EC function, we compared transcriptomic alterations induced by loss of GLUT1 by performing RNA sequencing analysis on freshly isolated ECs from P6 GLUT1EC-/- brains. At P6, 447 genes were differentially expressed between WT and GLUT1-/- ECs. Subsequent gene set enrichment analysis showed that within the most differentially expressed pathways, several ones were related to p53, as well as inflammatory related pathways.
2020-06-01 | GSE141924 | GEO
Project description:Transcriptome analysis of brain endothelial cells from adult EC-specific Glut1 knock-out mice as compared to wild type controls
| PRJNA595179 | ENA
Project description:Transcriptome analysis of brain endothelial cells from EC-specific Glut1 knock-out pups (P6) as compared to wild type controls
| PRJNA595178 | ENA
Project description:Enamelin is critical for proper dental enamel formation, and defects in the human enamelin gene cause autosomal dominant amelogenesis imperfecta. We used gene targeting to generate a knock-in mouse carrying a null allele of enamelin (Enam) that has a lacZ reporter gene replacing the Enam translation initiation site and gene sequences through exon 7. Correct targeting of the transgene was confirmed by Southern blotting and PCR analyses. No enamelin protein could be detected by Western blotting in the Enam-null mice. Histochemical 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside (X-gal) staining demonstrated ameloblast-specific expression of enamelin. The enamel of the Enam(+/-) mice was nearly normal in the maxillary incisors, but the mandibular incisors were discolored and tended to wear rapidly where they contacted the maxillary incisors. The Enam(-/-) mice showed no true enamel. Radiography, microcomputed tomography, and light and scanning electron microscopy were used to document changes in the enamel of Enam(-/-) mice but did not discern any perturbations of bone, dentin, or any other tissue besides the enamel layer. Although a thick layer of enamel proteins covered normal-appearing dentin of unerupted teeth, von Kossa staining revealed almost a complete absence of mineral formation in this protein layer. However, a thin, highly irregular, mineralized crust covered the dentin on erupted teeth, apparently arising from the formation and fusion of small mineralization foci (calcospherites) in the deeper part of the accumulated enamel protein layer. These results demonstrate ameloblast-specific expression of enamelin and reveal that enamelin is essential for proper enamel matrix organization and mineralization.
| S-EPMC2447669 | biostudies-literature
Project description:Paucity of the glucose transporter-1 (Glut1) protein resulting from haploinsufficiency of the SLC2A1 gene arrests cerebral angiogenesis and disrupts brain function to cause Glut1 deficiency syndrome (Glut1 DS). Restoring Glut1 to Glut1 DS model mice prevents disease, but the precise cellular sites of action of the transporter, its temporal requirements, and the mechanisms linking scarcity of the protein to brain cell dysfunction remain poorly understood. Here, we show that Glut1 functions in a cell-autonomous manner in the cerebral microvasculature to affect endothelial tip cells and, thus, brain angiogenesis. Moreover, brain endothelial cell-specific Glut1 depletion not only triggers a severe neuroinflammatory response in the Glut1 DS brain, but also reduces levels of brain-derived neurotrophic factor (BDNF) and causes overt disease. Reduced BDNF correlated with fewer neurons in the Glut1 DS brain. Controlled depletion of the protein demonstrated that brain pathology and disease severity was greatest when Glut1 scarcity was induced neonatally, during brain angiogenesis. Reducing Glut1 at later stages had mild or little effect. Our results suggest that targeting brain endothelial cells during early development is important to ensure proper brain angiogenesis, prevent neuroinflammation, maintain BDNF levels, and preserve neuron numbers. This requirement will be essential for any disease-modifying therapeutic strategy for Glut1 DS.
| S-EPMC7934852 | biostudies-literature
Project description:BackgroundGlobozoospermia is a male infertility phenotype characterized by the presence in the ejaculate of near 100% acrosomeless round-headed spermatozoa with normal chromosomal content. Following intracytoplasmic sperm injection (ICSI) these spermatozoa give a poor fertilization rate and embryonic development. We showed previously that most patients have a 200 kb homozygous deletion, which includes DPY19L2 whole coding sequence. Furthermore we showed that the DPY19L2 protein is located in the inner nuclear membrane of spermatids during spermiogenesis and that it is necessary to anchor the acrosome to the nucleus thus performing a function similar to that realized by Sun proteins within the LINC-complex (Linker of Nucleoskeleton and Cytoskeleton). SUN1 was described to be necessary for gametogenesis and was shown to interact with the telomeres. It is therefore possible that Dpy19l2 could also interact, directly or indirectly, with the DNA and modulate gene expression during spermatogenesis. In this study, we compared the transcriptome of testes from Dpy19l2 knock out and wild type mice in order to identify a potential deregulation of transcripts that could explain the poor fertilization potential of Dpy19l2 mutated spermatozoa.MethodsRNA was extracted from testes from DPY19L2 knock out and wild type mice. The transcriptome was carried out using GeneChip® Mouse Exon 1.0 ST Arrays. The biological processes and molecular functions of the differentially regulated genes were analyzed with the PANTHER software.ResultsA total of 76 genes were deregulated, 70 were up-regulated and 6 (including Dpy19l2) were down-regulated. These genes were found to be involved in DNA/RNA binding, structural organization, transport and catalytic activity.ConclusionsWe describe that an important number of genes are differentially expressed in Dpy19l2 mice. This work could help improving our understanding of Dpy19l2 functions and lead to a better comprehension of the molecular mechanism involved in spermatogenesis.
| S-EPMC4346239 | biostudies-literature
Project description:Background: Inactivation of microRNA-100 (miR-100) is involved in hepatocellular carcinoma (HCC) and miR-100 behaves as a tumor suppressor. To understand miR-100 function in HCC genesis and development in vivo, we developed hepatocyte-specific miR-100 deficient mice. Methods: Mice homozygous for floxed miR-100 allele that carried the Alb-Cre transgene (miR-100flox/floxAlb -Cre+) were developed by mating miR-100flox/flox mice with Alb-Cre+/+mice. The mice tails DNA were genotyped using the primers for LoxP sites and Cre recombinase, respectively. The specific deletion of miR-100 in the livers was verified by quantitative Real-time PCR (qRT-PCR). HE-staining was performed for histology analysis. Liver function was assessed by transaminase activity. The metabolic profiles of the hepatocytes were detected using a Seahorse XFe24 extracellular flux analyzer. The direct targets of miR-100 (such as IGF1R-β, mTOR and CDC25A) and HCC related protein (SHP-2) were detected by qRT-PCR and Western blot in liver tissues. Results: The resultant homozygous knockout mice with genotype of miR-100flox/flox-Alb-Cre+ showed an 80% decrease in hepatic miR-100 expression. In adult mice, miR-100 knockout has no effect on the liver function and morphology. In aged mice, HE staining showed that miR-100 knockout caused infiltration of inflammatory cells and expansion of hepatocellular nuclei. Consistently, liver function was impaired in miR-100 knockout aged mice as indicated by increased serum AST and ALT levels. The metabolic analysis demonstrated that the miR-100 knockout hepatocytes tend to adopt glycolysis. The expressions of the miR-100 target genes, such as IGF1R-β, CDC25A and mTOR, were increased. In addition, the known HCC related protein, SHP-2 also was up-regulated in the knockout livers. Conclusions: We successfully generated a miR-100 hepatocyte-specific knock-out mouse model. The malignant transformation related to HCC were observed in aged mice. Therefore, this model is suitable for investigating the mechanism of miR-100 inactivation contributing to HCC genesis in vivo.
| S-EPMC6606737 | biostudies-literature
Project description:Autism spectrum disorders (ASDs) are thought to involve neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many ASD-related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. Here, we show that early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like phenotypes in adult mice. Shank2–/– mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at post-weaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype–NMDAR hyperfunction–at an earlier pre-weaning stage (~P14). Moreover, this NMDAR hyperfunction at P14 is rapidly shifted to NMDAR hypofunction after weaning (~P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7?21) prevents the NMDAR hypofunction and autistic-like behaviors from manifesting at later stages (~P28 and P56). These results suggest that early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like behaviors in Shank2–/– mice, and that early correction of NMDAR function has the long-lasting effect of preventing autistic-like phenotypes from developing at later stages.
2021-04-20 | GSE82066 | GEO