title: Neurotrophin-3 null mutant mice display a postnatal motor neuropathy.
abstract: This paper examines early postnatal development of the neuromuscular system in mice with a null mutation in the gene for neurotrophin-3. We report that alpha-motoneurons at first develop substantially normally, despite a known 15% deficit in their somal size [Woolley et al. (1999)Neurosci. Lett., 272, 107-110.] and the absence of proprioceptive input [Ernfors et al. (1994)Cell, 77, 503-512]. At birth, motor axons have extended into the muscle, forming normal-looking neuromuscular junctions with focal accumulations of acetylcholine receptors. Detailed ultrastructural analysis does however, reveal subtle abnormalities at this time, particularly a decrease in the extent of occupancy of the postsynaptic site by nerve terminals, and a small but significant deficit in myofibre number. After the relative normality of this early neuromuscular development, there then occurs a catastrophic postnatal loss of motor nerve terminals, resulting in complete denervation of hindlimb muscles by P7. In systematic semi-serial samples through the entire muscle endplate zones, no neuromuscular junctions can be found. Intramuscular axons are fragmented, as shown by both electron microscopic observations and neurofilament immunohistochemistry, and alpha-bungarotoxin detection of acetylcholine receptors indicates dispersal of the junctional accumulation. At earlier times (postnatal days three and four) the terminal Schwann cells show ultrastructural abnormalities, and preliminary observations suggest marked disturbance of myelination. Based on comparison with other literature, the peripheral nerve degeneration seems unlikely to have arisen as a secondary effect of de-afferentation. We discuss whether the neural degeneration is secondary to the disturbance of Schwann cell function, or due directly to a loss of neurotrophin-3 based support of the motoneuron.
authors.affiliation: Department of Anatomy & Structural Biology, Otago School of Medical Sciences, University of Otago, PO Box 913, Dunedin, New Zealand.
authors.forename: Adele G
authors.initials: AG
authors.lastname: Woolley
authors.forename: Philip W
authors.initials: PW
authors.lastname: Sheard
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Duxson
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002038:Bungarotoxins / Q000378:metabolism; D004622:Embryo, Mammalian; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission / Q000379:methods; D024510:Muscle Development / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000473:pathology* / Q000502:physiology / Q000648:ultrastructure; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016900:Neurofilament Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000254:growth & development* / Q000473:pathology / Q000648:ultrastructure; D020933:Neurotrophin 3 / Q000235:genetics*; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D002038:Bungarotoxins; D016900:Neurofilament Proteins; D020933:Neurotrophin 3; D016708:Synaptophysin; C050934:neurofilament protein 150