title: A spontaneous mutation affects programmed cell death during development of the rat eye.
abstract: We have discovered a spontaneous mutation in the Sprague-Dawley rat with a novel eye phenotype that we have named Nuc1. The Nuc1 mutation behaves as a single semi-dominant locus with an intermediate phenotype in the heterozygotes. Heterozygotes exhibit nuclear cataracts. Homozygous Nuc1 rats are fully viable and have microphthalmia, retinal abnormalities and disruption of lens structure shortly before birth. The homozygous mutant shows no obvious pathology outside of the eye, indicating that the mutation is highly eye specific in its effects. An unusual feature of the mutation is that it prevents the normal programmed loss of nuclei from lens fiber cells, but does not affect the loss of other organelles. TUNEL, light, and electron microscopic studies show normal intact nuclei in lens fibers, in contrast to many other models with degenerate nuclei and unlike normal lenses where no such nuclei remain. The beaded filament protein, filensin, is down-regulated in fibers of Nuc1, while heat shock cognate 70 is up-regulated. Homozygous retinas are thicker than normal, and TUNEL labeling indicates roughly half the number of apoptotic cells compared to a wild-type retina. The transient layer of Chievitz persists in adult Nuc1 retina, indicative of delayed development. Hence, Nuc1 is a novel mutation that could be an eye-specific regulator of apoptosis.
authors.affiliation: Department of Ophthalmology, School of Medicine, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21287, USA. debasish@jhmi.edu
authors.forename: Debasish
authors.initials: D
authors.lastname: Sinha
authors.forename: Stacey
authors.initials: S
authors.lastname: Hose
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Rachel
authors.initials: R
authors.lastname: Neal
authors.forename: Madhumita
authors.initials: M
authors.lastname: Ghosh
authors.forename: Terrence P
authors.initials: TP
authors.lastname: O'Brien
authors.forename: Olof
authors.initials: O
authors.lastname: Sundin
authors.forename: Morton F
authors.initials: MF
authors.lastname: Goldberg
authors.forename: W Gerald
authors.initials: WG
authors.lastname: Robison
authors.forename: Paul
authors.initials: P
authors.lastname: Russell
authors.forename: Woo-Kuen
authors.initials: WK
authors.lastname: Lo
authors.forename: J
authors.initials: J
authors.lastname: Samuel Zigler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002467:Cell Nucleus / Q000648:ultrastructure; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005123:Eye / Q000254:growth & development* / Q000473:pathology; D005136:Eye Proteins / Q000032:analysis; D006579:Heterozygote; D020287:In Situ Nick-End Labeling / Q000379:methods; D007908:Lens, Crystalline / Q000166:cytology / Q000254:growth & development / Q000648:ultrastructure; D008854:Microscopy, Electron / Q000379:methods; D009154:Mutation / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology / Q000254:growth & development
chemical_list: D005136:Eye Proteins