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. 2018 Jul;209:54-62.
doi: 10.1016/j.cbpc.2018.03.006. Epub 2018 Mar 19.

Abnormal Nuclear Morphology Is Independent of Longevity in a zmpste24-deficient Fish Model of Hutchinson-Gilford Progeria Syndrome (HGPS)

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Abnormal Nuclear Morphology Is Independent of Longevity in a zmpste24-deficient Fish Model of Hutchinson-Gilford Progeria Syndrome (HGPS)

Yasuhiro Tonoyama et al. Comp Biochem Physiol C Toxicol Pharmacol. .
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Abstract

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.

Keywords: Aging; HGPS; Lamin; Medaka; Nuclear shape; Radiosensitivity; TILLING; Telomere; p53; zmpste24.

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