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The Journal of Neuroscience, June 1, 1998, 18(11):4076-4082
Non-Cell-Autonomous Photoreceptor Degeneration in rds
Mutant Mice Mosaic for Expression of a Rescue Transgene
Wojciech
Kedzierski1,
Dean
Bok2, and
Gabriel H.
Travis1
1 Department of Psychiatry and Program in Neuroscience,
University of Texas Southwestern Medical Center, Dallas, Texas
75235-9111, and 2 Department of Neurobiology, Jules Stein
Eye Institute and Brain Research Institute, University of California
Los Angeles School of Medicine, Los Angeles, California 90095
The inherited retinal dystrophies represent a large and
heterogenous group of hereditary neurodegenerations, for many of which, the molecular defect has been defined. However, the mechanism of cell
death has not been determined for any form of retinal degeneration. The
retinal degeneration slow (rds /)
mutation of mice is associated with nondevelopment of photoreceptor
outer segments and gradual death of photoreceptor cell bodies,
attributed to the absence of the outer segment protein rds/peripherin.
Here, we examined the effects of a transgene encoding normal
rds/peripherin that had integrated into the X-chromosome in male and
female rds/ mutant retinas. In 2-month-old
transgenic males and homozygous-transgenic females on
rds/, we observed virtually complete rescue of both the outer segment nondevelopment and photoreceptor degeneration. In
contrast, hemizygous-transgenic rds/ female
littermates showed patchy distributions of the transgene mRNA, by
in situ hybridization analysis, and of photoreceptor
cells that contain outer segments. This pattern is consistent with
random inactivation of the X-chromosome and mosaic expression of the
transgene. Surprisingly, we observed significant photoreceptor cell
loss in both transgene-expressing and nonexpressing patches in
hemizygous female retinas. These observations were supported by
nuclease protection analysis, which showed notably lower than predicted
levels of transgene mRNA in retinas from hemizygous females compared
with male and homozygous female littermates. This phenotype suggests an
important component of non-cell-autonomous photoreceptor death in
rds/ mutant mice. These results have significance to
both the etiology and potential treatment of human inherited retinal
degenerations.
Key words:
retinal degeneration; retinitis pigmentosa; rds; peripherin; X-chromosome; cell autonomous; transgene
Copyright © 1998 Society for Neuroscience 0270-6474/98/18114076-07$05.00/0
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