scholarly journals Notch1 is required for neuronal and glial differentiation in the cerebellum

Development ◽  
2002 ◽  
Vol 129 (2) ◽  
pp. 373-385 ◽  
Author(s):  
Simone Lütolf ◽  
Freddy Radtke ◽  
Michel Aguet ◽  
Ueli Suter ◽  
Verdon Taylor
Keyword(s):  
Central Nervous System ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Mammalian Brain ◽  
Glial Differentiation ◽  
Gene Ablation ◽  
Neuroepithelial Cells ◽  
Vertebrate Central Nervous System

The mechanisms that guide progenitor cell fate and differentiation in the vertebrate central nervous system (CNS) are poorly understood. Gain-of-function experiments suggest that Notch signaling is involved in the early stages of mammalian neurogenesis. On the basis of the expression of Notch1 by putative progenitor cells of the vertebrate CNS, we have addressed directly the role of Notch1 in the development of the mammalian brain. Using conditional gene ablation, we show that loss of Notch1 results in premature onset of neurogenesis by neuroepithelial cells of the midbrain-hindbrain region of the neural tube. Notch1-deficient cells do not complete differentiation but are eliminated by apoptosis, resulting in a reduced number of neurons in the adult cerebellum. We have also analyzed the effects of Notch1 ablation on gliogenesis in vivo. Our results show that Notch1 is required for both neuron and glia formation and modulates the onset of neurogenesis within the cerebellar neuroepithelium.

scholarly journals Müller glia provide essential tensile strength to the developing retina

2015 ◽  
Vol 210 (7) ◽  
pp. 1075-1083 ◽  
Author(s):  
Ryan B. MacDonald ◽  
Owen Randlett ◽  
Julia Oswald ◽  
Takeshi Yoshimatsu ◽  
Kristian Franze ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Glial Cells ◽  
Neural Retina ◽  
Force Microscopy ◽  
Tissue Integrity ◽  
Atomic Force ◽  
Neural Tissues ◽  
Vertebrate Central Nervous System

To investigate the cellular basis of tissue integrity in a vertebrate central nervous system (CNS) tissue, we eliminated Müller glial cells (MG) from the zebrafish retina. For well over a century, glial cells have been ascribed a mechanical role in the support of neural tissues, yet this idea has not been specifically tested in vivo. We report here that retinas devoid of MG rip apart, a defect known as retinoschisis. Using atomic force microscopy, we show that retinas without MG have decreased resistance to tensile stress and are softer than controls. Laser ablation of MG processes showed that these cells are under tension in the tissue. Thus, we propose that MG act like springs that hold the neural retina together, finally confirming an active mechanical role of glial cells in the CNS.

scholarly journals A Genome-Wide RNA Interference Screen Identifies a Differential Role of the Mediator CDK8 Module Subunits for GATA/ RUNX-Activated Transcription in Drosophila

2010 ◽  
Vol 30 (11) ◽  
pp. 2837-2848 ◽  
Author(s):  
Vanessa Gobert ◽  
Dani Osman ◽  
Stéphanie Bras ◽  
Benoit Augé ◽  
Muriel Boube ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Rna Interference ◽  
Cell Fate ◽  
Gata Factor ◽  
Hematopoietic System ◽  
Crystal Cell ◽  
Genome Wide ◽  
A Genome

ABSTRACT Transcription factors of the RUNX and GATA families play key roles in the control of cell fate choice and differentiation, notably in the hematopoietic system. During Drosophila hematopoiesis, the RUNX factor Lozenge and the GATA factor Serpent cooperate to induce crystal cell differentiation. We used Serpent/Lozenge-activated transcription as a paradigm to identify modulators of GATA/RUNX activity by a genome-wide RNA interference screen in cultured Drosophila blood cells. Among the 129 factors identified, several belong to the Mediator complex. Mediator is organized in three modules plus a regulatory “CDK8 module,” composed of Med12, Med13, CycC, and Cdk8, which has long been thought to behave as a single functional entity. Interestingly, our data demonstrate that Med12 and Med13 but not CycC or Cdk8 are essential for Serpent/Lozenge-induced transactivation in cell culture. Furthermore, our in vivo analysis of crystal cell development show that, while the four CDK8 module subunits control the emergence and the proliferation of this lineage, only Med12 and Med13 regulate its differentiation. We thus propose that Med12/Med13 acts as a coactivator for Serpent/Lozenge during crystal cell differentiation independently of CycC/Cdk8. More generally, we suggest that the set of conserved factors identified herein may regulate GATA/RUNX activity in mammals.

scholarly journals Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice

2018 ◽  
Vol 115 (20) ◽  
pp. 5253-5258 ◽  
Author(s):  
Hideyuki Yanai ◽  
Shiho Chiba ◽  
Sho Hangai ◽  
Kohei Kometani ◽  
Asuka Inoue ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Types ◽  
Type I ◽  
Type I Ifn ◽  
Cell Type ◽  
Gene Ablation ◽  
Cell Type Specific

IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3’s broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type-specific ablation of Irf3. Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4–IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.

Abstract 356: Krueppel-Like Factor 15 Regulates Wnt/β-Catenin Transcription and Controls Cardiac Progenitor Cell Fate in the Postnatal Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Claudia Noack ◽  
Maria P Zafiriou ◽  
Anke Renger ◽  
Hans J Schaeffer ◽  
Martin W Bergmann ◽  
...  
Keyword(s):  
Cell Fate ◽  
Transcriptional Activation ◽  
Progenitor Cell ◽  
Cellular Localization ◽  
Target Genes ◽  
Critical Role ◽  
Isolated Cells ◽  
Cardiac Progenitor Cell

Wnt/β-catenin signaling controls adult heart remodeling partly by regulating cardiac progenitor cell (CPC) differentiation. We now identified and characterized a novel cardiac interaction of the transcription factor Krueppel-like factor 15 (KLF15) with the Wnt/β-catenin signaling on adult CPCs. In vitro mutation, reporter gene assays and co-localization studies revealed that KLF15 requires two distinct domains for nuclear localization and for repression of β-catenin-mediated transcription. KLF15 had no effect on β-catenin stability or cellular localization, but interacted with its co-factor TCF4, which is required for activation of β-catenin target gene expression. Moreover, increased TCF4 ubiquitination was induced by KLF15. In line with this finding we found KLF15 to interact with the Nemo-like kinase, which was shown to phosphorylate and target TCF4 for degradation. In vivo analyses of adult Klf15 functional knock-out (KO) vs. wild-type (WT) mice showed a cardiac β-catenin-mediated transcriptional activation and reduced TCF4 degradation along with cardiac dysfunction assessed by echocardiography (n=10). FACS analysis of the CPC enriched-population of KO vs. WT mice revealed a significant reduction of cardiogenic-committed precursors identified as Sca1+/αMHC+ (0.8±0.2% vs. 1.8±0.1%) and Tbx5+ (3.5±0.3% vs. 5.2±0.5%). In contrast, endothelial Sca1+/CD31+ cells were significantly higher in KO mice (11.3±0.4% vs. 8.6±0.4%; n≥9). In addition, Sca1+ isolated cells of Klf15 KO showed increased RNA expression of endothelial markers von Willebrand Factor, CD105, and Flk1 along with upregulation of β-catenin target genes. CPCs co-cultured on adult fibroblasts resulted in increased endothelial Flk1 cells and reduction of αMHC and Hand1 cardiogenic cells in KO vs. WT CPCs (n=9). Treating these co-cultures with Quercetin, an inhibitor of nuclear β-catenin, resulted in partial rescue of the observed phenotype. This study uncovers a critical role of KLF15 for the maintenance of cardiac tissue homeostasis. Via inhibition of β-catenin transcription, KLF15 controls cardiomyogenic cell fate similar to embryonic cardiogenesis. This knowledge may provide a tool for activation of endogenous CPCs in the postnatal heart.

scholarly journals Present status and expectation of aristaless-related homeobox (ARX) in endocrine pancreas

2019 ◽  
Vol 63 (11-12) ◽  
pp. 579-587 ◽  
Author(s):  
Sai Xu ◽  
Ji-Ping Xu
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Endocrine Pancreas ◽  
Theoretical Foundation ◽  
Alpha Cell ◽  
Alpha Cells ◽  
Proliferation And Differentiation ◽  
Direct Target ◽  
Vertebrate Central Nervous System

The aristaless-related homeobox (ARX) gene has become one of most frequently mutated genes which is closely linked with development of the vertebrate central nervous system; however, the molecular and clinical bases of its function in the proliferation and differentiation of the endocrine pancreas have not, to date, been systematically characterized. ARX is considered as a regulator which determines endocrine cell fate and a bio-marker of the pancreatic α-cell. Disruption and mutation of ARX are found to lead to the deletion and reduction of α-cells both in mice models and in humans. Furthermore, expression of ARX is regulated by multiple transcription factors involved in development of the pancreas, such as Ngn3, Isl1, Nkx2.2 and Nkx6.1. Taken together, given the vital importance of glucagon in diabetes treatment, it is possible that ARX may down-regulate exorbitant glucagon levels by reducing the number of α-cells as a direct target; thus, the role of ARX in the maintenance of α-cell identity and quantity should be investigated and summarized. This article mainly focuses on the role of ARX in the endocrine pancreas, introduces the ARX-related animal model and transcription factors, and highlights the latest advances in our understanding in order to provide a clearer theoretical foundation for future scientific research.

scholarly journals Hyaluronan-Based Three-Dimensional Microenvironment Potently Induces Cardiovascular Progenitor Cell Populations

2013 ◽  
Vol 2013 ◽  
pp. 1-7
Author(s):  
Jessica M. Gluck ◽  
Jennifer Chyu ◽  
Connor Delman ◽  
Sepideh Heydarkhan-Hagvall ◽  
W. Robb MacLellan ◽  
...  
Keyword(s):  
Cell Fate ◽  
Progenitor Cell ◽  
Three Dimensional ◽  
Extrinsic Factors ◽  
Cell Fate Decisions ◽  
3D Microenvironment ◽  
Cell Niche ◽  
The Relationship ◽  
Stem Cell Niches

The relationship between stem cell niches in vivo and their surrounding microenvironment is still relatively unknown. Recent advances have indicated that extrinsic factors within the cardiovascular progenitor cell niche influence maintenance of a multipotent state as well as drive cell-fate decisions. We have previously shown the direct effects of extracellular matrix (ECM) proteins and have now investigated the effects of dimension on the induction of a cardiovascular progenitor cell (CPC) population. We have shown here that the three-dimensionality of a hyaluronan-based hydrogel greatly induces a CPC population, as marked by Flk-1. We have compared the effects of a 3D microenvironment to those of conventional 2D cell culture practices and have found that the 3D microenvironment potently induces a progenitor cell state.

scholarly journals Essential roles for Pot1b in HSC self-renewal and survival

Blood ◽  
2011 ◽  
Vol 118 (23) ◽  
pp. 6068-6077 ◽  
Author(s):  
Yang Wang ◽  
Mei-Feng Shen ◽  
Sandy Chang
Keyword(s):  
Progenitor Cell ◽  
Essential Role ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Wild Type ◽  
Telomere Shortening ◽  
Damage Response ◽  
First Time

Abstract Maintenance of mammalian telomeres requires both the enzyme telomerase and shelterin, which protect telomeres from inappropriately activating DNA damage response checkpoints. Dyskeratosis congenita is an inherited BM failure syndrome disorder because of defects in telomere maintenance. We have previously shown that deletion of the shelterin component Pot1b in the setting of telomerase haploinsufficiency results in rapid telomere shortening and fatal BM failure in mice, eliciting phenotypes that strongly resemble human syskeratosis congenita. However, it was unclear why BM failure occurred in the setting of Pot1b deletion. In this study, we show that Pot1b plays an essential role in HSC survival. Deletion of Pot1b results in increased apoptosis, leading to severe depletion of the HSC reserve. BM from Pot1bΔ/Δ mice cannot compete with BM from wild-type mice to provide multilineage reconstitution, indicating that there is an intrinsic requirement for Pot1b the maintenance of HSC function in vivo. Elimination of the p53-dependent apoptotic function increased HSC survival and significantly extended the lifespan of Pot1b-null mice deficient in telomerase function. Our results document for the first time the essential role of a component of the shelterin complex in the maintenance of HSC and progenitor cell survival.

scholarly journals Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy

2016 ◽  
Vol 371 (1700) ◽  
pp. 20150431 ◽  
Author(s):  
O. Ievglevskyi ◽  
D. Isaev ◽  
O. Netsyk ◽  
A. Romanov ◽  
M. Fedoriuk ◽  
...  
Keyword(s):  
Ion Channels ◽  
Hippocampal Neurons ◽  
Hippocampal Slices ◽  
Synaptic Activity ◽  
Mammalian Brain ◽  
Strong Increase ◽  
Life And Death ◽  
Acid Sensing Ion Channels

Acid-sensing ion channels (ASICs) play an important role in numerous functions in the central and peripheral nervous systems ranging from memory and emotions to pain. The data correspond to a recent notion that each neuron and many glial cells of the mammalian brain express at least one member of the ASIC family. However, the mechanisms underlying the involvement of ASICs in neuronal activity are poorly understood. However, there are two exceptions, namely, the straightforward role of ASICs in proton-based synaptic transmission in certain brain areas and the role of the Ca 2+ -permeable ASIC1a subtype in ischaemic cell death. Using a novel orthosteric ASIC antagonist, we have found that ASICs specifically control the frequency of spontaneous inhibitory synaptic activity in the hippocampus. Inhibition of ASICs leads to a strong increase in the frequency of spontaneous inhibitory postsynaptic currents. This effect is presynaptic because it is fully reproducible in single synaptic boutons attached to isolated hippocampal neurons. In concert with this observation, inhibition of the ASIC current diminishes epileptic discharges in a low Mg 2+ model of epilepsy in hippocampal slices and significantly reduces kainate-induced discharges in the hippocampus in vivo . Our results reveal a significant novel role for ASICs. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.

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