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MBNL deficiency in spinal motor neurons compromises neuromuscular junction maintenance and gait coordination: implication for Myotonic Dystrophy
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International audience. Myotonic dystrophy type 1 (DM1) is a neuromuscular disease characterised by myotonia, progressive muscle weakness and atrophy, cardiac defects as well as cognitive impairments. DM1 is caused by the expression of CTG repeat expansions in the 3’UTR of the DMPK gene; subsequent mutant transcripts, containing expanded CUG repeats, aggregate as ribonuclear inclusions that sequester muscleblind-like (MBNL) RNA-binding proteins, impairing their functions in various tissues. RNA metabolism abnormalities observed in affected DM1 tissues are mainly attributable to MBNL family loss-of-function: MBNL1 is mostly expressed in skeletal muscles but also found in the brain; MBNL2 is predominantly expressed in the brain and MBNL3 during embryonic development. While most studies on DM1 muscle pathology have focused on the skeletal muscle itself, prior reports suggest an impaired communication between motor neurons (MN) and skeletal muscle. To assess the role of MBNL in MN, we generated a conditional mouse model invalidated for Mbnl1 and Mbnl2 in MN (dKO). dKO mice develop progressive motor abnormalities associated with neuromuscular junction (NMJ) alterations indicating that MBNL compound loss-of-function in MN significantly affects NMJ structure and function. As NMJ are unaltered in young dKO mice, deficiency in NMJ maintenance rather than development may be responsible for NMJ abnormalities observed in older mice. transcriptome analysis in the spinal cord of dKO mice suggests synaptic transmission and NMJ homeostasis may be altered by the loss of Mbnl1 and Mbnl2 in MN. Altogether our work will help for a better knowledge of DM1 physiopathology.
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