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

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

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Axons / metabolism
  • Brain / embryology
  • Brain / pathology
  • Cell Line
  • Classical Lissencephalies and Subcortical Band Heterotopias / genetics
  • Classical Lissencephalies and Subcortical Band Heterotopias / pathology*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Muscle, Skeletal / pathology
  • Neuromuscular Junction / embryology*
  • Neuromuscular Junction / genetics
  • Neuromuscular Junction / metabolism*
  • Neuromuscular Junction / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Receptors, Cholinergic / metabolism

Substances

  • Microtubule-Associated Proteins
  • Neuropeptides
  • Receptors, Cholinergic
  • doublecortin protein