TY - JOUR
T1 - A spontaneous mutation affects programmed cell death during development of the rat eye
AU - Sinha, Debasish
AU - Hose, Stacey
AU - Zhang, Cheng
AU - Neal, Rachel
AU - Ghosh, Madhumita
AU - O'Brien, Terrence P.
AU - Sundin, Olof
AU - Goldberg, Morton F.
AU - Robison, W. Gerald
AU - Russell, Paul
AU - Lo, Woo Kuen
AU - Zigler, J. Samuel
N1 - Funding Information:
We would like to thank Drs Joram Piatigorsky, Peggy Zelenka, Janine Davis, Stanislav Tomarev, Steven Bassnett, Panagiotis Tsonis and Colin Barnstable for critical reading and discussion regarding this manuscript. We are grateful to Melissa Weishaar and staff members at Spring Valley Laboratories, Woodbine, Maryland for taking care of the experimental animals. We thank Dr Paul Fitzgerald for the Filensin antibody. This work was supported in part by a pediatric ophthalmology research grant from the Knights Templar Eye Foundation Inc. (to DS), National Eye Institute EY05314 (to WKL) and funds from The Raymond Kwok Research Fund, The Guerrieri fund for retinal research at The Wilmer Eye Institute and Research to Prevent Blindness (an unrestricted grant to Wilmer Eye Institute). This manuscript is dedicated in memory of Dr. W. Gerald Robison Yr., whom we will deeply miss.
PY - 2005/3
Y1 - 2005/3
N2 - 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.
AB - 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.
KW - Abnormal development of retina
KW - Apoptosis
KW - Eye development
KW - Lens denucleation
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U2 - 10.1016/j.exer.2004.09.014
DO - 10.1016/j.exer.2004.09.014
M3 - Article
C2 - 15721615
AN - SCOPUS:13844298728
SN - 0014-4835
VL - 80
SP - 323
EP - 335
JO - Experimental eye research
JF - Experimental eye research
IS - 3
ER -