title: Embryonic senescence and laminopathies in a progeroid zebrafish model.
abstract: BACKGROUND
  Mutations that disrupt the conversion of prelamin A to mature lamin A cause the rare genetic disorder Hutchinson-Gilford progeria syndrome and a group of laminopathies. Our understanding of how A-type lamins function in vivo during early vertebrate development through aging remains limited, and would benefit from a suitable experimental model. The zebrafish has proven to be a tractable model organism for studying both development and aging at the molecular genetic level. Zebrafish show an array of senescence symptoms resembling those in humans, which can be targeted to specific aging pathways conserved in vertebrates. However, no zebrafish models bearing human premature senescence currently exist.
  
  
  RESULTS
  We describe the induction of embryonic senescence and laminopathies in zebrafish harboring disturbed expressions of the lamin A gene (LMNA). Impairments in these fish arise in the skin, muscle and adipose tissue, and sometimes in the cartilage. Reduced function of lamin A/C by translational blocking of the LMNA gene induced apoptosis, cell-cycle arrest, and craniofacial abnormalities/cartilage defects. By contrast, induced cryptic splicing of LMNA, which generates the deletion of 8 amino acid residues lamin A (zlamin A-Δ8), showed embryonic senescence and S-phase accumulation/arrest. Interestingly, the abnormal muscle and lipodystrophic phenotypes were common in both cases. Hence, both decrease-of-function of lamin A/C and gain-of-function of aberrant lamin A protein induced laminopathies that are associated with mesenchymal cell lineages during zebrafish early development. Visualization of individual cells expressing zebrafish progerin (zProgerin/zlamin A-Δ37) fused to green fluorescent protein further revealed misshapen nuclear membrane. A farnesyltransferase inhibitor reduced these nuclear abnormalities and significantly prevented embryonic senescence and muscle fiber damage induced by zProgerin. Importantly, the adult Progerin fish survived and remained fertile with relatively mild phenotypes only, but had shortened lifespan with obvious distortion of body shape.
  
  
  CONCLUSIONS
  We generated new zebrafish models for a human premature aging disorder, and further demonstrated the utility for studying laminopathies. Premature aging could also be modeled in zebrafish embryos. This genetic model may thus provide a new platform for future drug screening as well as genetic analyses aimed at identifying modifier genes that influence not only progeria and laminopathies but also other age-associated human diseases common in vertebrates.
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Eriko
authors.initials: E
authors.lastname: Koshimizu
authors.forename: Shintaro
authors.initials: S
authors.lastname: Imamura
authors.forename: Jie
authors.initials: J
authors.lastname: Qi
authors.forename: Jamal
authors.initials: J
authors.lastname: Toure
authors.forename: Delgado M
authors.initials: DM
authors.lastname: Valdez
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Carr
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Hanai
authors.forename: Shuji
authors.initials: S
authors.lastname: Kishi
mesh_terms: D000375:Aging / Q000187:drug effects / Q000473:pathology*; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects; D002356:Cartilage / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology*; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics*; D008060:Lipodystrophy / Q000150:complications / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008969:Molecular Sequence Data; D009132:Muscles / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011371:Progeria / Q000150:complications* / Q000473:pathology*; D011498:Protein Precursors / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*
chemical_list: D034904:Lamin Type A; D050505:Mutant Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011498:Protein Precursors; C485184:enhanced green fluorescent protein; C090764:prelamin A; D049452:Green Fluorescent Proteins