Mutant Human Embryonic Stem Cells Reveal Neurite and Synapse Formation Defects in Type 1 Myotonic Dystrophy

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting a variety of organs, including the central nervous system. By using neuronal progeny derived from human embryonic stem cells carrying the causal DM1 mutation, we have identified an early developmental defect in genes involved in neurite formation and the establishment of neuromuscular connections. Differential gene expression profiling and quantitative RT-PCR revealed decreased expression of two members of the SLITRK family in DM1 neural cells and in DM1 brain biopsies. In addition, DM1 motoneuron/muscle cell cocultures showed alterations that are consistent with the known role of SLITRK genes in neurite outgrowth, neuritogenesis, and synaptogenesis. Rescue and knockdown experiments suggested that the functional defects can be directly attributed to SLITRK misexpression. These neuropathological mechanisms may be clinically significant for the functional changes in neuromuscular connections associated with DM1.

miR-322/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte specification

“…Ectopic Celf1 impairs myoblast differentiation (50,51). Neurite overgrowth was recently observed in DM1 ESCs, suggesting uncontrolled neural differentiation (52). Here we show that Celf1 impairs cardiomyocyte differentiation but promotes neural lineages.…”

In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

“…of examples illustrate how such cells, retrieved from genetically selected donors carrying the causal mutation of a monogenic disorder, may reproduce disease-associated phenotypes (22)(23)(24)(25)(26). Thus, we used two human embryonic stem cell (hESC) lines derived from embryos characterized as mutant gene carriers for NF1 during a preimplantation diagnosis procedure, to explore mechanisms associated with hyperpigmentation in melanocytes and potential treatments for the pathological phenotype.…”

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

“…For example, pre-implantation genetically diagnosed embryos have been used to analyze molecular and functional defects in hESCsderived neurons carrying a mutant gene responsible for fragile X (Eiges et al, 2007) and in motoneurons with myotonic dystrophy type 1 (DM1) (Marteyn et al, 2011). Other early childhood-onset monogenic disorders, such as Rett syndrome, familial dysautonomia disorder and spinal muscular atrophy, have been studied following the generation of hiPSCs from patients, and a defective neuronal phenotype associated with the expression of the mutant gene (Ebert et al, 2009;Kim et al, 2011;Lee et al, 2009).…”