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The Journal of Neuroscience, October 3, 2007, 27(40):10887-10894; doi:10.1523/JNEUROSCI.0903-07.2007

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Cellular/Molecular
Bim Expression Indicates the Pathway to Retinal Cell Death in Development and Degeneration

Francesca Doonan,^1 * Maryanne Donovan,^1 * Violeta Gomez-Vicente,¹ Philippe Bouillet,² and Thomas G. Cotter¹

¹Tumour Biology Laboratory, Biochemistry Department, Bioscience Research Institute, University College Cork, Cork, Republic of Ireland, and ²The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia

Correspondence should be addressed to Thomas G. Cotter at the above address. Email: t.cotter{at}ucc.ie

Programmed cell death (PCD) during development of the mouse retina involves activation of the mitochondrial pathway. Previous work has shown that the multidomain Bcl-2 family proteins Bax and Bak are fundamentally involved in this process. To induce mitochondrial membrane permeabilization, Bax and Bak require that prosurvival members of the family be inactivated by binding of "BH3-only" members. We showed previously that the BH3-only protein BimEL is highly expressed during postnatal retinal development but decreases dramatically thereafter. The purpose of this study was to investigate a possible role for Bim, in retinal development and degeneration, upstream of Bax and Bak. Bim^–/– mice analyzed for defective retinal development exhibit an increase in retinal thickness and a delay in PCD, thereby confirming a role for Bim. We also demonstrate that in response to certain death stimuli, bim^+/+ retinal explants upregulate BimEL leading to caspase activation and cell death, whereas bim^–/– explants are resistant to apoptosis. Finally, we analyzed Bim expression in the retinal degeneration (rd) mouse, an in vivo model of retinal degeneration. Bim isoforms, which decrease during development, are not reexpressed during retinal degeneration and ultimately photoreceptor cells die by a caspase-independent mechanism. Thus, we conclude that in cases in which BimEL is reexpressed during pathological cell death, developmental cell death pathways are reactivated. However, the absence of BimEL expression correlates with caspase-independent death in the rd model.

Key words: Bim; retina; development; apoptosis; caspase; rd

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Received Feb. 28, 2007; revised July 26, 2007; accepted July 26, 2007.

Correspondence should be addressed to Thomas G. Cotter at the above address. Email: t.cotter{at}ucc.ie

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				B. A. Berkowitz, M. Gradianu, S. Schafer, Y. Jin, A. Porchia, R. Iezzi, and R. Roberts Ionic Dysregulatory Phenotyping of Pathologic Retinal Thinning with Manganese-Enhanced MRI Invest. Ophthalmol. Vis. Sci., July 1, 2008; 49(7): 3178 - 3184. [Abstract] [Full Text] [PDF]

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