title: Crosstalk between Notch and Sonic hedgehog signaling in a mouse model of amyotrophic lateral sclerosis.
abstract: The developmental morphogen Sonic hedgehog (Shh) may continue to play a sustaining role in adult motor neurons, of potential relevance to motor neuron diseases including amyotrophic lateral sclerosis. The Shh signaling pathway is incompletely understood and interactions with other signaling pathways are possible. We focus here on Notch, and first show that there is an almost linear reduction in light output from a Gli reporter in Shh Light II cells in the presence of increasing concentrations of the Notch inhibitor DAPT (r=0.982). Second, in the spinal cord of mutant superoxide dismutase mice, but not control mice, a key marker of Notch signaling changes with age. Before the onset of clinical signs, the Notch intracellular domain is expressed predominantly in motor neurons, but by 125 days of age, Notch intracellular domain expression is markedly reduced in motor neurons and increased in neighboring astroglia. Third, there is a parallel reduction in Gli protein expression in mutant superoxide dismutase mouse spinal motor neurons, consistent with the observed reduction in Notch signaling and also a redistribution of Gli away from the nucleus. Thus, there is a reduction in motor neuronal Notch signaling and associated changes in Shh signaling, occurring coincidentally with disease expression, that may contribute toward the dysfunction and death of motor neurons in amyotrophic lateral sclerosis.
authors.affiliation: aDepartment of Medicine, McMaster University, Hamilton bTechnical Client and Project Manager Biopharmaceutical Services, SGS Life Sciences Services Canada, Mississauga, Ontario, Canada.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Ma
authors.forename: Anna
authors.initials: A
authors.lastname: Drannik
authors.forename: Fan
authors.initials: F
authors.lastname: Jiang
authors.forename: Randy
authors.initials: R
authors.lastname: Peterson
authors.forename: John
authors.initials: J
authors.lastname: Turnbull
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D003959:Diamines / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology; D000075746:Zinc Finger Protein Gli2 / Q000378:metabolism
chemical_list: C000612000:24-diamino-5-phenylthiazole; D039481:CD11b Antigen; C428808:CRCT1 protein, human; D003959:Diamines; D004791:Enzyme Inhibitors; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D051880:Receptors, Notch; D013844:Thiazoles; D000075746:Zinc Finger Protein Gli2; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase