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

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 neu...

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Bibliographic Details
Published in:Cell stem cell 2011-04, Vol.8 (4), p.434-444
Main Authors: Marteyn, Antoine, Maury, Yves, Gauthier, Morgane M., Lecuyer, Camille, Vernet, Remi, Denis, Jérôme A., Pietu, Geneviève, Peschanski, Marc, Martinat, Cécile
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cell differentiation, maturation, development, hematopoiesis
Cell physiology
Diseases of striated muscles. Neuromuscular diseases
Embryonic Stem Cells - pathology
Embryonic Stem Cells - ultrastructure
Fundamental and applied biological sciences. Psychology
Gene Expression Profiling
Gene Expression Regulation, Developmental
Humans
Medical sciences
Membrane Proteins - genetics
Molecular and cellular biology
Mutation
Myotonic Dystrophy - genetics
Myotonic Dystrophy - pathology
Nerve Tissue Proteins - genetics
Neurites - pathology
Neurology
Synapses - pathology
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Summary: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. ► Neural differentiation of hESC lines from myotonic dystrophy type 1 (DM1) embryos ► Coculture assays reveal defects in neuritis and neuromuscular connections ► Gene expression analysis highlights reduction in SLITRK family proteins ► SLITRK knockdown mimics the phenotype, and SLITRK overexpression rescues it
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2011.02.004