title: mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by myotonic dystrophy type 1.
abstract: Patients with myotonic dystrophy type 1 exhibit a diversity of symptoms that affect many different organs. Among these are cognitive dysfunctions, the origin of which has remained elusive, partly because of the difficulty in accessing neural cells. Here, we have taken advantage of pluripotent stem cell lines derived from embryos identified during a pre-implantation genetic diagnosis for mutant-gene carriers, to produce early neuronal cells. Functional characterization of these cells revealed reduced proliferative capacity and increased autophagy linked to mTOR signaling pathway alterations. Interestingly, loss of function of MBNL1, an RNA-binding protein whose function is defective in DM1 patients, resulted in alteration of mTOR signaling, whereas gain-of-function experiments rescued the phenotype. Collectively, these results provide a mechanism by which DM1 mutation might affect a major signaling pathway and highlight the pertinence of using pluripotent stem cells to study neuronal defects.
authors: INSERM/UEVE U-861, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 5 rue Henri Desbruères, 91030 Evry cedex, France.
authors: Jérôme Alexandre
authors: JA
authors: Denis
authors: Morgane
authors: M
authors: Gauthier
authors: Latif
authors: L
authors: Rachdi
authors: Sophie
authors: S
authors: Aubert
authors: Karine
authors: K
authors: Giraud-Triboult
authors: Pauline
authors: P
authors: Poydenot
authors: Alexandra
authors: A
authors: Benchoua
authors: Benoite
authors: B
authors: Champon
authors: Yves
authors: Y
authors: Maury
authors: Christine
authors: C
authors: Baldeschi
authors: Raphael
authors: R
authors: Scharfmann
authors: Geneviève
authors: G
authors: Piétu
authors: Marc
authors: M
authors: Peschanski
authors: Cécile
authors: C
authors: Martinat
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D053595:Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Human embryonic stem cells; Myotonic dystrophy type 1; Neural stem cells; Pathological modeling; mTOR signaling pathways