Photoreceptor cells in the vitiligo mouse die by apoptosis: TRPM- 2/clusterin expression is increased in the neural retina and in the retinal pigment epithelium

Sylvia B Smith, N. Bora, D. McCool, G. Kutty, P. Wong, R. K. Kutty, B. Wiggert

Research output: Contribution to journalArticle

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Abstract

Purpose. To determine the mechanism of photoreceptor cell death in the vitiligo mouse, a model of retinal degeneration in which the genetic defect is not retina specific but is instead caused by single point mutation in the microphthalmia (mi) gene that codes for a basic helix-loop-helix DNA transcription factor. Methods. Detection of apoptotic cells was performed in fixed retinal tissue using the TUNEL assay in animals 1, 2, 4, 6, 8, 16, 32, 50, and 52 weeks. Electron microscopic analysis was used to confirm the morphologic hallmarks of apoptosis, anti Southern blot analysis was used to detect internucleosomal DNA fragmentation. Additionally, the expression of a gene associated with apoptosis, TRPM-2/clusterin, was examined. Results. At ages beyond the time of normal retinal programmed cell death, vitiligo retinas had significantly more TUNEL-positive photoreceptor cells and more photoreceptor cells with condensed chromatin than controls. DNA internucleosomal fragmentation ladders were present in vitiligo retinas even as late as 15 weeks, a time well beyond developmental apoptosis in controls. TRPM-2/clusterin mRNA levels in vitiligo neural retinas were similar to controls initially but were two times greater than controls by 12 weeks. Surprisingly, TRPM-2/clusterin mRNA levels were elevated in the retinal pigment epithelium in the migrant; the expression at one week was two times greater than normals and remained elevated for many months, even though retinal pigment epithelial cells showed no morphologic evidence of apoptosis. Conclusions. The morphologic anti biochemical data suggest that photoreceptor cells die by apoptosis in vitiligo mice. The increased retinal TRPM- 2/clusterin mRNA levels may be a direct response to these events. The increased expression of this gene in the retinal pigment epithelium, however, may reflect its role in tissue regression and membrane remodeling. Mechanisms by which the mi gene defect might result in the vitiligo retinopathy are proposed.

Original languageEnglish (US)
Pages (from-to)2193-2201
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume36
Issue number11
StatePublished - Jan 1 1995

Fingerprint

Clusterin
Photoreceptor Cells
Vitiligo
Retinal Pigment Epithelium
Retina
Apoptosis
Microphthalmos
In Situ Nick-End Labeling
DNA Fragmentation
Messenger RNA
Cell Death
Basic Helix-Loop-Helix Transcription Factors
Gene Expression
Retinal Degeneration
Retinal Pigments
Southern Blotting
Point Mutation
Genes
Chromatin
Epithelial Cells

Keywords

  • TRPM-2
  • apoptosis
  • clusterin
  • microphthalmia
  • photoreceptor cells
  • retinal degeneration
  • vitiligo

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Photoreceptor cells in the vitiligo mouse die by apoptosis : TRPM- 2/clusterin expression is increased in the neural retina and in the retinal pigment epithelium. / Smith, Sylvia B; Bora, N.; McCool, D.; Kutty, G.; Wong, P.; Kutty, R. K.; Wiggert, B.

In: Investigative Ophthalmology and Visual Science, Vol. 36, No. 11, 01.01.1995, p. 2193-2201.

Research output: Contribution to journalArticle

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abstract = "Purpose. To determine the mechanism of photoreceptor cell death in the vitiligo mouse, a model of retinal degeneration in which the genetic defect is not retina specific but is instead caused by single point mutation in the microphthalmia (mi) gene that codes for a basic helix-loop-helix DNA transcription factor. Methods. Detection of apoptotic cells was performed in fixed retinal tissue using the TUNEL assay in animals 1, 2, 4, 6, 8, 16, 32, 50, and 52 weeks. Electron microscopic analysis was used to confirm the morphologic hallmarks of apoptosis, anti Southern blot analysis was used to detect internucleosomal DNA fragmentation. Additionally, the expression of a gene associated with apoptosis, TRPM-2/clusterin, was examined. Results. At ages beyond the time of normal retinal programmed cell death, vitiligo retinas had significantly more TUNEL-positive photoreceptor cells and more photoreceptor cells with condensed chromatin than controls. DNA internucleosomal fragmentation ladders were present in vitiligo retinas even as late as 15 weeks, a time well beyond developmental apoptosis in controls. TRPM-2/clusterin mRNA levels in vitiligo neural retinas were similar to controls initially but were two times greater than controls by 12 weeks. Surprisingly, TRPM-2/clusterin mRNA levels were elevated in the retinal pigment epithelium in the migrant; the expression at one week was two times greater than normals and remained elevated for many months, even though retinal pigment epithelial cells showed no morphologic evidence of apoptosis. Conclusions. The morphologic anti biochemical data suggest that photoreceptor cells die by apoptosis in vitiligo mice. The increased retinal TRPM- 2/clusterin mRNA levels may be a direct response to these events. The increased expression of this gene in the retinal pigment epithelium, however, may reflect its role in tissue regression and membrane remodeling. Mechanisms by which the mi gene defect might result in the vitiligo retinopathy are proposed.",
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AU - McCool, D.

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