Background and Purpose: 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. Methods and Results: 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. Conclusion: 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.
[1]Fudan Univ, Huashan Hosp, Dept Neurol, 12 Wulumuqi Zhong Rd, Shanghai 200040, Peoples R China;
[2]Fudan Univ, Inst Neurol, Shanghai, Peoples R China;
[3]Mayo Clin, Dept Neurosci, Jacksonville, FL USA;
[4]Harbin Med Univ, Affiliated Hosp 4, Dept Neurol, Harbin, Heilongjiang Pr, Peoples R China;
[5]Hong Kong Univ Sci & Technol, Shenzhen Peking Univ, Shenzhen Key Lab Neuronal Struct Biol, Biomed Res Inst,Med Ctr, Shenzhen, Guangdong, Peoples R China
(8.0+极速模式)