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Neuromuscul Disord. 2015 Jun;25(6):461-73. doi: 10.1016/j.nmd.2015.01.012. Epub 2015 Feb 26.

A critical and previously unsuspected role for doublecortin at the neuromuscular junction in mouse and human.

Author information

1
Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; CNRS UMR 8194, F75270,Paris, France.
2
Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; Service commun de Microscopie, F75270 Paris, France.
3
Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; INSERM U1016, Hôpital Necker Enfants Malades, Paris, France.
4
Sorbonne Université, Université Pierre et Marie Curie, F75005 Paris, France; UM CR18, Neurosciences Paris Seine, INSERM, UMR-S 1130, F75005 Paris, France; CNRS, UMR 8246, Neuroscience Paris Seine, F75005 Paris, France.
5
Sorbonne Université, Université Pierre et Marie Curie, F75005 Paris, France; INSERM UMR-S 839, F75005 Paris, France; Institut du Fer à Moulin, F75005 Paris, France.
6
Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; CNRS UMR 8194, F75270,Paris, France. Electronic address: Claire.legay@parisdescartes.fr.

Abstract

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 NMJ. 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.

KEYWORDS:

Doublecortin; Lissencephaly type I; Neuromuscular junction; Synapse formation

PMID:
25817838
DOI:
10.1016/j.nmd.2015.01.012
[Indexed for MEDLINE]

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