mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by Myotonic Dystrophy Type1

Abstract

Patients with Myotonic Dystrophy type 1 exhibit a diversity of symptoms that affect many different organs. Among those are cognitive dysfunctions, the origin of which has remained elusive due in part to 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 as mutant gene-carriers, in order to differentiate cells along the neural lineage. Functional characterization of these cells revealed reduced proliferative capacity and increased autophagy linked to mTOR signaling pathway alterations. Interestingly, loss of function of MBNL1, a RNA-binding protein whose function is defective in DM1 patients, resulted in the mTOR signaling alteration 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.