Journal
NEUROMUSCULAR DISORDERS
Volume 25, Issue 6, Pages 461-473Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.nmd.2015.01.012
Keywords
Neuromuscular junction; Doublecortin; Lissencephaly type I; Synapse formation
Categories
Funding
- AFM
- CNRS
- Universite Paris Descartes
- INSERM
- Agence Nationale de la Recherche [ANR-08-MNP-013]
- Avenir program
- UPMC
- Fondation Bettencourt Schueller
- Conseil Regional, Ile-de-France
- Fondation Jerome Lejeune
- European Union [602531]
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Mutations in the microtubule-associated protein doublecortin (DCX) cause type I (X-linked or XLIS) lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in females, with defects in neuron migration during development affecting cortical lamination. We found that besides its well-established expression in migrating neurons of the brain, doublecortin (Dcx in mice) is also expressed in motor neurons and skeletal muscle in embryonic neuromuscular junctions (NMJs), raising the possibility of a role in synaptogenesis. Studies with whole-mount preparations of embryonic mouse diaphragm revealed that loss of Dcx leads to abnormal presynaptic arborization and a significantly increased incidence of short axonal extensions beyond innervated acetylcholine receptor (AChR) clusters in the developing NMI. This phenotype, albeit relatively mild, suggests that Dcx contributes to a stop/stabilizing signal at the synapse, which normally limits further axonal growth following establishment of synaptic contact with the postsynaptic element. Importantly, we also identified abnormal and denervated NMJs in a muscle biopsy from a 16-year-old female patient with SBH, showing both profound presynaptic and postsynaptic morphological defects. Overall, these combined results point to a critical role of doublecortin in the formation of the NMJ. (C) 2015 Elsevier B.V. All rights reserved.
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