title: A critical and previously unsuspected role for doublecortin at the neuromuscular junction in mouse and human.
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.
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; CNRS UMR 8194, F75270,Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Bourgeois
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; CNRS UMR 8194, F75270,Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Messéant
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; CNRS UMR 8194, F75270,Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Kordeli
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; Service commun de Microscopie, F75270 Paris, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Petit
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; CNRS UMR 8194, F75270,Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Delers
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; INSERM U1016, Hôpital Necker Enfants Malades, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Bahi-Buisson
authors.affiliation: 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.
authors.forename: V
authors.initials: V
authors.lastname: Bernard
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; CNRS UMR 8194, F75270,Paris, France.
authors.forename: S M
authors.initials: SM
authors.lastname: Sigoillot
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; INSERM U1016, Hôpital Necker Enfants Malades, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Gitiaux
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Stouffer
authors.affiliation: 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.
authors.forename: F
authors.initials: F
authors.lastname: Francis
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, F75270 Paris, France; CNRS UMR 8194, F75270,Paris, France. Electronic address: Claire.legay@parisdescartes.fr.
authors.forename: C
authors.initials: C
authors.lastname: Legay
mesh_terms: D000293:Adolescent; D000818:Animals; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000196:embryology / Q000473:pathology; D002460:Cell Line; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics / Q000473:pathology*; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D009469:Neuromuscular Junction / Q000196:embryology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism
chemical_list: C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D011950:Receptors, Cholinergic
keywords: Doublecortin; Lissencephaly type I; Neuromuscular junction; Synapse formation