mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by myotonic dystrophy type 1

作者：Denis Jerome Alexandre; Gauthier Morgane; Rachdi Latif; Aubert Sophie; Giraud Triboult Karine; Poydenot Pauline; Benchoua Alexandra; Champon Benoite; Maury Yves; Baldeschi Christine; Scharfmann Raphael; Pietu Genevieve; Peschanski Marc; Martinat Cecile^*

来源：Journal of Cell Science, 2013, 126(8): 1763-1772.

DOI：10.1242/jcs.116285

• Neural stem cells
• Human embryonic stem cells
• Pathological modeling
• Myotonic dystrophy type 1
• mTOR signaling pathways

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.

• 出版日期2013-4-15