Sox2 Is Required for Embryonic Development of the Ventral
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ARTICLE Received 3 May 2012 | Accepted 5 Nov 2012 | Published 4 Dec 2012 DOI: 10.1038/ncomms2254 The RB family is required for the self-renewal and survival of human embryonic stem cells Jamie F. Conklin1,2,3, Julie Baker2,3 & Julien Sage1,2,3 The mechanisms ensuring the long-term self-renewal of human embryonic stem cells are still only partly understood, limiting their use in cellular therapies. Here we found that increased activity of the RB cell cycle inhibitor in human embryonic stem cells induces cell cycle arrest, differentiation and cell death. Conversely, inactivation of the entire RB family (RB, p107 and p130) in human embryonic stem cells triggers G2/M arrest and cell death through functional activation of the p53 pathway and the cell cycle inhibitor p21. Differences in E2F target gene activation upon loss of RB family function between human embryonic stem cells, mouse embryonic stem cells and human fibroblasts underscore key differences in the cell cycle regulatory networks of human embryonic stem cells. Finally, loss of RB family function pro- motes genomic instability in both human and mouse embryonic stem cells, uncoupling cell cycle defects from chromosomal instability. These experiments indicate that a homeostatic level of RB activity is essential for the self-renewal and the survival of human embryonic stem cells. 1 Department of Pediatrics, Stanford Medical School, Stanford, California 94305, USA. 2 Department of Genetics, Stanford Medical School, Stanford, California 94305, USA. 3 Institute for Stem Cell Biology and Regenerative Medicine, Stanford Medical School, Stanford, California 94305, USA. Correspondence and requests for materials should be addressed to J.S. -
Author Manuscript Faculty of Biology and Medicine Publication
Serveur Académique Lausannois SERVAL serval.unil.ch Author Manuscript Faculty of Biology and Medicine Publication This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination. Published in final edited form as: Title: Sexual dimorphism in cancer. Authors: Clocchiatti A, Cora E, Zhang Y, Dotto GP Journal: Nature reviews. Cancer Year: 2016 May Volume: 16 Issue: 5 Pages: 330-9 DOI: 10.1038/nrc.2016.30 In the absence of a copyright statement, users should assume that standard copyright protection applies, unless the article contains an explicit statement to the contrary. In case of doubt, contact the journal publisher to verify the copyright status of an article. Sexual dimorphism in cancer Andrea Clocchiatti1+, Elisa Cora2+, Yosra Zhang1,2 and G. Paolo Dotto1,2* 1Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; 2Department of Biochemistry, University of Lausanne, Epalinges, CH-1066, Switzerland + These authors contributed equally to the work * Corresponding author: G. Paolo Dotto email: [email protected] 1 Abstract The incidence of many cancer types is significantly higher in the male than female populations, with associated differences in survival. Occupational and/or behavioral factors are well known underlying determinants. However, cellular/molecular differences between the two sexes are also likely to be important. We are focusing here on the complex interplay that sexual hormones and sex chromosomes can have in intrinsic control of cancer initiating cell populations, tumor microenvironment and systemic determinants of cancer development like the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment. -
Human Autologous Ipsc–Derived Dopaminergic Progenitors Restore Motor Function in Parkinson’S Disease Models
Human autologous iPSC–derived dopaminergic progenitors restore motor function in Parkinson’s disease models Bin Song, … , Jeffrey S. Schweitzer, Kwang-Soo Kim J Clin Invest. 2020;130(2):904-920. https://doi.org/10.1172/JCI130767. Research Article Neuroscience Stem cells Graphical abstract Find the latest version: https://jci.me/130767/pdf RESEARCH ARTICLE The Journal of Clinical Investigation Human autologous iPSC–derived dopaminergic progenitors restore motor function in Parkinson’s disease models Bin Song,1,2 Young Cha,1,2 Sanghyeok Ko,1,2 Jeha Jeon,1,2 Nayeon Lee,1,2 Hyemyung Seo,1,2,3 Kyung-Joon Park,1 In-Hee Lee,4,5 Claudia Lopes,1,2 Melissa Feitosa,1,2 María José Luna,1,2 Jin Hyuk Jung,1,2 Jisun Kim,1,2,3 Dabin Hwang,1,2 Bruce M. Cohen,1 Martin H. Teicher,1 Pierre Leblanc,1,2 Bob S. Carter,6 Jeffrey H. Kordower,7 Vadim Y. Bolshakov,1 Sek Won Kong,4,5 Jeffrey S. Schweitzer,6 and Kwang-Soo Kim1,2 1Department of Psychiatry and 2Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA. 3Department of Molecular and Life Sciences, Hanyang University, Ansan, Korea. 4Department of Pediatrics, 5Computational Health Informatics Program, Boston Children’s Hospital, and 6Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. 7Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. Parkinson’s disease (PD) is a neurodegenerative disorder associated with loss of striatal dopamine, secondary to degeneration of midbrain dopamine (mDA) neurons in the substantia nigra, rendering cell transplantation a promising therapeutic strategy. -
AIRE Is a Critical Spindle-Associated Protein in Embryonic Stem Cells Bin Gu1, Jean-Philippe Lambert2, Katie Cockburn1, Anne-Claude Gingras2,3, Janet Rossant1,3*
RESEARCH ARTICLE AIRE is a critical spindle-associated protein in embryonic stem cells Bin Gu1, Jean-Philippe Lambert2, Katie Cockburn1, Anne-Claude Gingras2,3, Janet Rossant1,3* 1Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada; 2Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, Canada; 3Department of Molecular Genetics, University of Toronto, Toronto, Canada Abstract Embryonic stem (ES) cells go though embryo-like cell cycles regulated by specialized molecular mechanisms. However, it is not known whether there are ES cell-specific mechanisms regulating mitotic fidelity. Here we showed that Autoimmune Regulator (Aire), a transcription coordinator involved in immune tolerance processes, is a critical spindle-associated protein in mouse ES(mES) cells. BioID analysis showed that AIRE associates with spindle-associated proteins in mES cells. Loss of function analysis revealed that Aire was important for centrosome number regulation and spindle pole integrity specifically in mES cells. We also identified the c-terminal LESLL motif as a critical motif for AIRE’s mitotic function. Combined maternal and zygotic knockout further revealed Aire’s critical functions for spindle assembly in preimplantation embryos. These results uncovered a previously unappreciated function for Aire and provide new insights into the biology of stem cell proliferation and potential new angles to understand fertility defects in humans carrying Aire mutations. DOI: 10.7554/eLife.28131.001 *For correspondence: janet. [email protected] Introduction Competing interests: The Self-renewal capability, defined as the ability of cells to proliferate while sustaining differentiation authors declare that no potential, is one of the defining features of stem cells (Martello and Smith, 2014). -
Mediator of DNA Damage Checkpoint 1 (MDC1) Is a Novel Estrogen Receptor Co-Regulator in Invasive 6 Lobular Carcinoma of the Breast 7 8 Evelyn K
bioRxiv preprint doi: https://doi.org/10.1101/2020.12.16.423142; this version posted December 16, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 1 Running Title: MDC1 co-regulates ER in ILC 2 3 Research article 4 5 Mediator of DNA damage checkpoint 1 (MDC1) is a novel estrogen receptor co-regulator in invasive 6 lobular carcinoma of the breast 7 8 Evelyn K. Bordeaux1+, Joseph L. Sottnik1+, Sanjana Mehrotra1, Sarah E. Ferrara2, Andrew E. Goodspeed2,3, James 9 C. Costello2,3, Matthew J. Sikora1 10 11 +EKB and JLS contributed equally to this project. 12 13 Affiliations 14 1Dept. of Pathology, University of Colorado Anschutz Medical Campus 15 2Biostatistics and Bioinformatics Shared Resource, University of Colorado Comprehensive Cancer Center 16 3Dept. of Pharmacology, University of Colorado Anschutz Medical Campus 17 18 Corresponding author 19 Matthew J. Sikora, PhD.; Mail Stop 8104, Research Complex 1 South, Room 5117, 12801 E. 17th Ave.; Aurora, 20 CO 80045. Tel: (303)724-4301; Fax: (303)724-3712; email: [email protected]. Twitter: 21 @mjsikora 22 23 Authors' contributions 24 MJS conceived of the project. MJS, EKB, and JLS designed and performed experiments. JLS developed models 25 for the project. EKB, JLS, SM, and AEG contributed to data analysis and interpretation. SEF, AEG, and JCC 26 developed and performed informatics analyses. MJS wrote the draft manuscript; all authors read and revised the 27 manuscript and have read and approved of this version of the manuscript. -
Cell Reprogramming Technologies for Treatment And
CELL REPROGRAMMING TECHNOLOGIES FOR TREATMENT AND UNDERSTANDING OF GENETIC DISORDERS OF MYELIN by ANGELA MARIE LAGER Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Thesis advisor: Paul J Tesar, PhD Department of Genetics and Genome Sciences CASE WESTERN RESERVE UNIVERSITY May 2015 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Angela Marie Lager Candidate for the Doctor of Philosophy degree*. (signed) Ronald A Conlon, PhD (Committee Chair) Paul J Tesar, PhD (Advisor) Craig A Hodges, PhD Warren J Alilain, PhD (date) 31 March 2015 *We also certify that written approval has been obtained from any proprietary material contained therein. TABLE OF CONTENTS Table of Contents……………………………………………………………………….1 List of Figures……………………………………………………………………………4 Acknowledgements……………………………………………………………………..7 Abstract…………………………………………………………………………………..8 Chapter 1: Introduction and Background………………………………………..11 1.1 Overview of mammalian oligodendrocyte development in the spinal cord and myelination of the central nervous system…………………..11 1.1.1 Introduction……………………………………………………..11 1.1.2 The establishment of the neuroectoderm and ventral formation of the neural tube…………………………………..12 1.1.3 Ventral patterning of the neural tube and specification of the pMN domain in the spinal cord……………………………….15 1.1.4 Oligodendrocyte progenitor cell production through the process of gliogenesis ………………………………………..16 1.1.5 Oligodendrocyte progenitor cell to oligodendrocyte differentiation…………………………………………………...22 -
The GATA2 Transcription Factor Negatively Regulates the Proliferation of Neuronal Progenitors
RESEARCH ARTICLE 2155 Development 133, 2155-2165 (2006) doi:10.1242/dev.02377 The GATA2 transcription factor negatively regulates the proliferation of neuronal progenitors Abeer El Wakil*, Cédric Francius*,†, Annie Wolff, Jocelyne Pleau-Varet† and Jeannette Nardelli†,§ Postmitotic neurons are produced from a pool of cycling progenitors in an orderly fashion that requires proper spatial and temporal coordination of proliferation, fate determination, differentiation and morphogenesis. This probably relies on complex interplay between mechanisms that control cell cycle, specification and differentiation. In this respect, we have studied the possible implication of GATA2, a transcription factor that is involved in several neuronal specification pathways, in the control of the proliferation of neural progenitors in the embryonic spinal cord. Using gain- and loss-of-function manipulations, we have shown that Gata2 can drive neural progenitors out of the cycle and, to some extent, into differentiation. This correlates with the control of cyclin D1 transcription and of the expression of the p27/Kip1 protein. Interestingly, this functional aspect is not only associated with silencing of the Notch pathway but also appears to be independent of proneural function. Consistently, GATA2 also controls the proliferation capacity of mouse embryonic neuroepithelial cells in culture. Indeed, Gata2 inactivation enhances the proliferation rate in these cells. By contrast, GATA2 overexpression is sufficient to force such cells and neuroblastoma cells to stop dividing but not to drive either type of cell into differentiation. Furthermore, a non-cell autonomous effect of Gata2 expression was observed in vivo as well as in vitro. Hence, our data have provided evidence for the ability of Gata2 to inhibit the proliferation of neural progenitors, and they further suggest that, in this regard, Gata2 can operate independently of neuronal differentiation. -
Regulation of Adult Neurogenesis in Mammalian Brain
International Journal of Molecular Sciences Review Regulation of Adult Neurogenesis in Mammalian Brain 1,2, 3, 3,4 Maria Victoria Niklison-Chirou y, Massimiliano Agostini y, Ivano Amelio and Gerry Melino 3,* 1 Centre for Therapeutic Innovation (CTI-Bath), Department of Pharmacy & Pharmacology, University of Bath, Bath BA2 7AY, UK; [email protected] 2 Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK 3 Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, 00133 Rome, Italy; [email protected] (M.A.); [email protected] (I.A.) 4 School of Life Sciences, University of Nottingham, Nottingham NG7 2HU, UK * Correspondence: [email protected] These authors contributed equally to this work. y Received: 18 May 2020; Accepted: 7 July 2020; Published: 9 July 2020 Abstract: Adult neurogenesis is a multistage process by which neurons are generated and integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. Neurogenesis plays a fundamental role in postnatal brain, where it is required for neuronal plasticity. Moreover, perturbation of adult neurogenesis contributes to several human diseases, including cognitive impairment and neurodegenerative diseases. The interplay between extrinsic and intrinsic factors is fundamental in regulating neurogenesis. Over the past decades, several studies on intrinsic pathways, including transcription factors, have highlighted their fundamental role in regulating every stage of neurogenesis. However, it is likely that transcriptional regulation is part of a more sophisticated regulatory network, which includes epigenetic modifications, non-coding RNAs and metabolic pathways. -
Abbit Monoclonal Igg Antibody Against Human, Mouse SOX1
Anti-Human SOX1 Antibody, Clone EPR4766 Antibodies Rabbit monoclonal IgG antibody against human, mouse SOX1 Catalog #60095 0.1 mL Product Description The EPR4766 antibody reacts with SOX1, also known as SRY (sex determining region Y)-box 1, an ~40 kDa nuclear transcription factor belonging to the SRY-related HMG-box family. SOX1 is involved in regulating development of the central nervous system and is an early marker for neuroectodermal differentiation in the embryo. Its expression is down-regulated during differentiation in many neuronal subtypes. SOX1 is also a useful marker for identifying embryonic and somatic neuronal progenitor cells (NPCs), in concert with other markers such as SOX2 and SOX9. SOX1 is thought to promote self-renewal in NPCs, whereas it functions in other cell types to promote differentiation. There is evidence that SOX1 plays a role in tumor suppression by binding to ß-catenin and attenuating the WNT signaling pathway, and in mice it plays an essential role in lens development by regulating expression of γ-crystallins. The EPR4766 antibody does not cross-react with rat SOX1. Target Antigen Name: SOX1 Alternative Names: Sox-1, SRY (sex determining region Y)-box 1, SRY-related HMG-box Gene ID: 6656 Species Reactivity: Human, Mouse Host Species: Rabbit Clonality: Monoclonal Clone: EPR4766 Isotype: IgG Immunogen: Synthetic peptide corresponding to the partial amino acid sequence of human SOX1 Conjugate: Unconjugated Applications Verified: ICC, IF, IHC, WB Reported: ICC, IF, IHC, WB Special Applications: This antibody clone has been verified for labeling neural stem and progenitor cells grown with STEMdiff™ Neural Induction Medium (Catalog #05835), STEMdiff™ Neural Progenitor Medium (Catalog #05833), NeuroCult™ NS-A Proliferation Kit (Human; Catalog #05751) and NeuroCult™ Proliferation Kit (Mouse; Catalog #05702). -
Stoichiometric and Temporal Requirements of Oct4, Sox2, Klf4, and C-Myc Expression for Efficient Human Ipsc Induction and Differentiation
Stoichiometric and temporal requirements of Oct4, Sox2, Klf4, and c-Myc expression for efficient human iPSC induction and differentiation Eirini P. Papapetroua,b, Mark J. Tomishimac,d, Stuart M. Chambersc, Yvonne Micae, Evan Reeda,b, Jayanthi Menona,f, Viviane Tabara,f, Qianxing Mog, Lorenz Studera,c, and Michel Sadelaina,b,1 aCenter for Cell Engineering, bMolecular Pharmacology and Chemistry and cDevelopmental Biology Programs, dSKI Stem Cell Research Facility, eGerstner Sloan-Kettering Graduate School, and Departments of fNeurosurgery and gEpidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065 Communicated by Mark Ptashne, Memorial Sloan–Kettering Cancer Center, New York, NY, May 1, 2009 (received for review April 8, 2009) Human-induced pluripotent stem cells (hiPSCs) are generated from purposes remains controversial (20). Furthermore, the significance somatic cells by ectopic expression of the 4 reprogramming factors of vector silencing for reprogramming and its impact on differen- (RFs) Oct-4, Sox2, Klf4, and c-Myc. To better define the stoichiometric tiation is unclear. Although it has been proposed that silencing of requirements and dynamic expression patterns required for success- factor expression is required for successful reprogramming and ful hiPSC induction, we generated 4 bicistronic lentiviral vectors multilineage differentiation (3, 21, 22), it remains unclear whether encoding the 4 RFs co-expressed with discernable fluorescent pro- vector silencing constitutes a requirement or an epiphenomenon of teins. Using this system, we define the optimal stoichiometry of RF the reprogramming process. expression to be highly sensitive to Oct4 dosage, and we demonstrate Here we present a vector system for iPSC induction that allows the impact that variations in the relative ratios of RF expression exert for simultaneous real-time tracking of expression of the 4 individual on the efficiency of hiPSC induction. -
Long Noncoding RNA Lncpgcr Mediated by TCF7L2 Regulates Primordial Germ Cell Formation in Chickens
animals Article Long Noncoding RNA LncPGCR Mediated by TCF7L2 Regulates Primordial Germ Cell Formation in Chickens Jingyi Jiang 1, Chen Chen 1, Shaoze Cheng 1, Xia Yuan 1, Jing Jin 1, Chen Zhang 1, Xiaolin Sun 1 , Jiuzhou Song 2 , Qisheng Zuo 1, Yani Zhang 1, Guohong Chen 1 and Bichun Li 1,* 1 Key Laboratory of Animal Breeding Reproduction and Molecular Design for Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, Jiangsu, China; [email protected] (J.J.); [email protected] (C.C.); [email protected] (S.C.); [email protected] (X.Y.); [email protected] (J.J.); [email protected] (C.Z.); [email protected] (X.S.); [email protected] (Q.Z.); [email protected] (Y.Z.); [email protected] (G.C.) 2 Animal & Avian Sciences, University of Maryland, College Park, MD 20741, USA; [email protected] * Correspondence: [email protected] Simple Summary: The potential of primordial germ cells (PGCs) for multidirectional differentiation, together with their unique regeneration ability, makes them one of the most promising seed cells in clinical medicine and tissue engineering research. However, not enough PGCs can be obtained to meet the demand, which limits their application. We defined a novel long noncoding RNA (lncRNA) mediated by epigenetics, which could activate the miR-6577-5p/Btrc pathway to promote the formation of PGCs. The technical system we have established is a useful tool to obtain sufficient PGCs for scientific research. Our study offers great theoretical and practical value in the production of transgenic animals or genomic imprinting in poultry. -
NIH Public Access Author Manuscript Curr Opin Immunol
NIH Public Access Author Manuscript Curr Opin Immunol. Author manuscript; available in PMC 2012 April 1. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Curr Opin Immunol. 2011 April ; 23(2): 198±206. doi:10.1016/j.coi.2010.11.007. Aire and T cell Development Mark S. Andersona,* and Maureen A. Sub,* a Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA b Inflammatory Diseases Institute and Department of Pediatrics, University of North Carolina, Chapel Hill, Chapel Hill, NC Abstract In the thymus, developing T cells that react against self-antigens with high affinity are deleted in the process of negative selection. An essential component of this process is the display of self- antigens, including those whose expression are usually restricted to specific tissues, to developing T cells within the thymus. The Autoimmune Regulator (Aire) gene plays a critical role in the expression of tissue specific self-antigens within the thymus, and disruption of Aire function results in spontaneous autoimmunity in both humans and mice. Recent advances have been made in our understanding of how Aire influences the expression of thousands of tissue-specific antigens in the thymus. Additional roles of Aire, including roles in chemokine and cytokine expression, have also been revealed. Factors important in the differentiation of Aire-expressing medullary thymic epithelial cells have been defined. Finally, the identity of antigen presenting cells in negative selection, including the role of medullary thymic epithelial cells in displaying tissue specific antigens to T cells, has also been clarified.