Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA126707 | ENA |
REPOSITORIES: ENA
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Project description:We have generated transgenic mice with tetracycline-regulated conditional expression of a constitutively active allele of FoxO3 under the control of the forebrain-specific CaMKIIa promoter. In adult animals, there was a reduction of brain weight by 30% and an almost complete loss of the dorsal dentate gyrus with normal cortical layering. Interestingly, the adult mice showed motor hyperactivity and a selective loss of long-term memory with normal spatial learning. We observed enhanced apoptosis starting from day E10.5. Performing microarray expression analyses and Q-PCR validation with E12.5 forebrain RNA, we observed an over-representation of thalamic markers and an under-representation of cortical markers in transgenic as compared to control animals. Immunohistochemical data show a loss of progenitors in the lateral ventricles. Up-regulation of Pik3ip1 as a target gene of FoxO3 could be responsible for the observed increase in apoptosis. The obtained forebrain expression signature is reminiscent of a Pax6 knockdown phenotype showing that expression of this FoxO3 allele during development affected neural progenitor survival and overall brain development. Conclusion: Neural progenitors are vulnerable to constitutively active FoxO3-induced apoptosis. We sought to determine the transcriptional differences in forebrains from E12.5 mice expressing a constitutively active alleleof FoxO3 under the control of the forebrain-specific CaMKIIa promoter. To this end two time-pregnant dams were sacrificed 12 days after the vaginal plug was detected, and the embryos were prepared. Visual staging of the embryos confirmed their age. Genotyping and luciferase measurements were performed in order to assess presence and acitivity of the transgenes.
2012-09-13 | E-GEOD-21089 | biostudies-arrayexpress
Project description:We have generated transgenic mice with tetracycline-regulated conditional expression of a constitutively active allele of FoxO3 under the control of the forebrain-specific CaMKIIa promoter. In adult animals, there was a reduction of brain weight by 30% and an almost complete loss of the dorsal dentate gyrus with normal cortical layering. Interestingly, the adult mice showed motor hyperactivity and a selective loss of long-term memory with normal spatial learning. We observed enhanced apoptosis starting from day E10.5. Performing microarray expression analyses and Q-PCR validation with E12.5 forebrain RNA, we observed an over-representation of thalamic markers and an under-representation of cortical markers in transgenic as compared to control animals. Immunohistochemical data show a loss of progenitors in the lateral ventricles. Up-regulation of Pik3ip1 as a target gene of FoxO3 could be responsible for the observed increase in apoptosis. The obtained forebrain expression signature is reminiscent of a Pax6 knockdown phenotype showing that expression of this FoxO3 allele during development affected neural progenitor survival and overall brain development. Conclusion: Neural progenitors are vulnerable to constitutively active FoxO3-induced apoptosis.
2012-09-13 | GSE21089 | GEO
Project description:Constitutively Active Foxo3 in Oocytes Preserves Ovarian Reserve in Mice
| PRJNA193681 | ENA
Project description:During female reproductive life, the reserve of ovarian follicles is reduced by maturation and atresia until menopause ensues. Foxo3 is required to maintain the ovarian reserve in mice. We asked if overexpression of a constitutively active FOXO3 protein can increase long-lasting ovarian reproductive capacity in mice. Trangenic vs non-transgenic mice onto Foxo3+/- vs Foxo3-/- genotype
2013-06-08 | E-GEOD-45389 | biostudies-arrayexpress
Project description:During female reproductive life, the reserve of ovarian follicles is reduced by maturation and atresia until menopause ensues. Foxo3 is required to maintain the ovarian reserve in mice. We asked if overexpression of a constitutively active FOXO3 protein can increase long-lasting ovarian reproductive capacity in mice.
2013-06-08 | GSE45389 | GEO
Project description:The unique mental abilities of humans are rooted in the immensely expanded and folded neocortex, which reflects the expansion of neural progenitors, especially basal progenitors including basalradial glia (bRGs, also called outer RGs) and intermediate progenitor cells (IPCs). Here, we show that constitutively active Shh signaling expanded basal progenitors and induced folding in the otherwise smooth mouse neocortex, whereas the loss of Shh signaling decreased the number of basal progenitors and the size of the neocortex. SHH signaling was strongly active in the human fetal neocortex but not in the mouse embryonic neocortex, and blocking SHH signaling in humancerebral organoids decreased the number of bRGs. Mechanistically, Shh signaling increased theinitial generation and self-renewal of bRGs as well as increasing IPC proliferation. Thus, robust SHH signaling in the human fetal neocortex may contribute to basal progenitor expansion and neocortical growth and folding.
2016-05-23 | GSE80958 | GEO
Project description:Overexpression of constitutively active Ikkb and/or loss of Stat3 in murine esophageal epithelium
| PRJNA718966 | ENA
Project description:MCF7 and MDA-MB-231 breast cancer cell lines were cultured in DMEM-F12 containing 10% FBS (Lonza) 100U/ml penicillin and 100 µg/ml streptomycin (Lonza). Transfecting third generation packaging vectors using Poly-ethylenimine into HEK293T cells generated lentiviral particles (17). MCF7 and MDA-MB-231 cells were stably transduced with lentivirus containing pINDUCER20-FOXO3.A3, allowing doxycycline induced expression of constitutively active FOXO3 (FOXO3.A3). Cells were treated with 20% FBS or 10 µM PI3K inhibitor LY294002 (Selleckchem) for 16 hours to activate and inactivate the endogenous PI3K pathway, respectively. FOXO3.A3 expression was induced by 16 hours treatment with 10 ng/ml doxycycline.
2018-06-06 | GSE113479 | GEO
Project description:Fate and behaviour of neural progenitor cells is tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells, govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multi-enzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors (APs) and reduced progenitor proliferation. Further, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell (ESC)-derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity and progenitor expansion in the developing human forebrain. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor cell polarity and lipid metabolism.
2022-01-14 | PXD026110 | Pride
Project description:FOXO3 is an evolutionally conserved transcription factor that has been linked to longevity. Here we asked whether human stem cells could be functionally enhanced by engineering them to express an activated form of FOXO3. This was accomplished via HDAdV-mediated gene editing of human embryonic stem cells. These cells were then differentiated into a range of vascular cell types, as FOXO3 has been shown to play a protective role in the cardiovascular system. FOXO3-enhanced vascular cells exhibited delayed senescence and increased resistance to oxidative injuries, compared with wild type cells. When tested in a therapeutic context, FOXO3-enhanced human mesenchymal stem cells promoted vasculature regeneration in a mouse model of ischemic injury, and were resistant to tumorigenic transformation, both in vitro and in vivo. Mechanistically, constitutively active FOXO3 conferred cytoprotection by transcriptionally downregulating CSRP1. Taken together, our findings provide mechanistic insights into FOXO3-mediated vascular protection, and indicate that FOXO3 activation may provide a means for generating more effective and safe biomaterials for cell replacement therapies.
2019-03-12 | GSE116277 | GEO