Abnormal nuclear morphology is independent of longevity in a zmpste24-deficient fish model of Hutchinson-Gilford progeria syndrome (HGPS)

Yasuhiro Tonoyama, Minori Shinya, Atsushi Toyoda, Takeshi Kitano, Atsunori Oga, Toshiyuki Nishimaki, Takafumi Katsumura, Hiroki Oota, Miles T. Wan, Bill W.P. Yip, Mok O.L. Helen, Shinichi Chisada, Tomonori Deguchi, Doris W.T. Au, Kiyoshi Naruse, Yasuhiro Kamei, Yoshihito Taniguchi

研究成果: Article査読

2 被引用数 (Scopus)

抄録

Lamin is an intermediate protein underlying the nuclear envelope and it plays a key role in maintaining the integrity of the nucleus. A defect in the processing of its precursor by a metalloprotease, ZMPSTE24, results in the accumulation of farnesylated prelamin in the nucleus and causes various diseases, including Hutchinson-Gilford progeria syndrome (HGPS). However, the role of lamin processing is unclear in fish species. Here, we generated zmpste24-deficient medaka and evaluated their phenotype. Unlike humans and mice, homozygous mutants did not show growth defects or lifespan shortening, despite lamin precursor accumulation. Gonadosomatic indices, blood glucose levels, and regenerative capacity of fins were similar in 1-year-old mutants and their wild-type (WT) siblings. Histological examination showed that the muscles, subcutaneous fat tissues, and gonads were normal in the mutants at the age of 1 year. However, the mutants showed hypersensitivity to X-ray irradiation, although p53target genes, p21 and mdm2, were induced 6 h after irradiation. Immunostaining of primary cultured cells from caudal fins and visualization of nuclei using H2B-GFP fusion proteins revealed an abnormal nuclear shape in the mutants both in vitro and in vivo. The telomere lengths were significantly shorter in the mutants compared to WT. Taken together, these results suggest that zmpste24-deficient medaka phenocopied HGPS only partially and that abnormal nuclear morphology and lifespan shortening are two independent events in vertebrates.

本文言語English
ページ(範囲)54-62
ページ数9
ジャーナルComparative Biochemistry and Physiology Part - C: Toxicology and Pharmacology
209
DOI
出版ステータスPublished - 2018 7

ASJC Scopus subject areas

  • 生化学
  • 生理学
  • 毒物学
  • 細胞生物学
  • 健康、毒物学および変異誘発

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