title: Dync1h1 Mutation Causes Proprioceptive Sensory Neuron Loss and Impaired Retrograde Axonal Transport of Dorsal Root Ganglion Neurons.
abstract: Sprawling (Swl) is a radiation-induced mutation which has been identified to have a nine base pair deletion in dynein heavy chain 1 (DYNC1H1: encoded by a single gene Dync1h1). This study is to investigate the phenotype and the underlying mechanism of the Dync1h1 mutant.
  
  
  
  To display the phenotype of Swl mutant mice, we examined the embryos of homozygous (Swl/Swl) and heterozygous (Swl/+) mice and their postnatal dorsal root ganglion (DRG) of surviving Swl/+ mice. The Swl/+ mice could survive for a normal life span, while Swl/Swl could only survive till embryonic (E) 8.5 days. Excessive apoptosis of Swl/+ DRG neurons was revealed during E11.5-E15.5 days, and the peak rate was at E13.5 days. In vitro study of mutated DRG neurons showed impaired retrograde transport of dynein-driven nerve growth factor (NGF). Mitochondria, another dynein-driven cargo, demonstrated much slower retrograde transport velocity in Swl/+ neurons than in wild-type (WT) neurons. Nevertheless, the Swl, Loa, and Cra mutations did not affect homodimerization of DYNC1H1.
  
  
  
  The Swl/Swl mutation of Dync1h1 gene led to embryonic mal-development and lethality, whereas the Swl/+ DRG neurons demonstrated deficient retrograde transport in dynein-driven cargos and excessive apoptosis during mid- to late-developmental stages. The underlying mechanism of the mutation may not be due to impaired homodimerization of DYNC1H1.
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.|Institute of Neurology, Fudan University, Shanghai, China.|Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Neurology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Qian
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Deng
authors.initials: D
authors.lastname: Bo
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong Province, China.
authors.forename: Yan-Xin
authors.initials: YX
authors.lastname: Lu
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong Province, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong Province, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.|Institute of Neurology, Fudan University, Shanghai, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.|Institute of Neurology, Fudan University, Shanghai, China.
authors.forename: Xiang-Jun
authors.initials: XJ
authors.lastname: Chen
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D001370:Axonal Transport / Q000235:genetics*; D002478:Cells, Cultured; D056445:Cytoplasmic Dyneins / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D020932:Nerve Growth Factor; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D059008:Time-Lapse Imaging; D014162:Transfection
chemical_list: C516947:Dync1h1 protein, mouse; D049452:Green Fluorescent Proteins; D020932:Nerve Growth Factor; D056445:Cytoplasmic Dyneins
keywords: Dynein heavy chain; Mouse mutant; Neuron loss; Retrograde transport; Sprawling mutation