May 2004
Volume 45, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2004
Transcriptional regulation of pro–apoptotic Bcl–2 family members during retinal development and photoreceptor cell death.
Author Affiliations & Notes
  • T.G. Cotter
    Dept. of Biochemistry, University College, Cork, Ireland
  • Footnotes
    Commercial Relationships  T.G. Cotter, None.
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Investigative Ophthalmology & Visual Science May 2004, Vol.45, 4670. doi:
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      T.G. Cotter; Transcriptional regulation of pro–apoptotic Bcl–2 family members during retinal development and photoreceptor cell death. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4670.

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Abstract

Abstract: : Purpose: We have previously demonstrated that photoreceptor cell death, via apoptosis, in several mouse models of retinal degeneration occurs independently of caspase activation and the lack of cytochrome–c release is an apical event in these systems. The purpose of this study is to investigate in vivo whether members of the Bcl–2 family of proteins play a role in controlling the release of cytochrome c and importantly whether this control is developmentally regulated. Methods: Cell death via apoptosis was monitored via TUNEL staining of fixed retinas. Retinas were dissected from mice at daily intervals up to post–natal day 15 and protein extracts prepared. These extracts were then subjected to western blotting and stained to look for expression for Bcl–2 family members. RT–PCR analysis was used to look at their respective mRNA expression. Cytochrome c release from mitochondria was monitored in cytosol and mitochondrial extracts. Results: In this study we show that photoreceptors from early postnatal retinas are capable of executing a caspase–dependent cell death pathway that displays typical features of apoptosis including cytochrome c release, caspase–3 activation and DNA fragmentation. To determine why these cells employ two different pathways of cell death depending on their stage of development, we examined the expression pattern of several members of the Bcl–2 family. We show that pro apoptotic members of the Bcl–2 family such as Bax, Bak, Bid, and the three isoforms of Bim are down regulated during postnatal retinal development. Importantly, BimS is only expressed up to postnatal day 10, which correlates with the progression of developmental apoptosis. We show that Bax is completely absent from adult retina mitochondria, potentially explaining the lack of cytochrome c release and caspase activation in the adult retina following various stimuli. This is further supported by the demonstration that mitochondria isolated from adult retina are less susceptible to BH3–induced cytochrome c release than postnatal day 10 retina. Conclusions: Our results indicate that the transcriptional regulation of ‘death genes’ such as pro apoptotic Bcl–2 family members in fully differentiated tissues may act as a mechanism by which post mitotic cells retain tight control of apoptosis.

Keywords: apoptosis/cell death • retinal degenerations: cell biology • photoreceptors 
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