Bim expression indicates the pathway to retinal cell death in development and degeneration.

Abstract

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.

• Authors: Francesca Doonan, Maryanne Donovan, Violeta Gomez-Vicente, Philippe Bouillet, Thomas G Cotter
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 27 Issue 40 Pg. 10887-94 (Oct 03 2007) ISSN: 1529-2401 [Electronic] United States
• PMID: 17913922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Bcl-2-Like Protein 11
• Bcl2l11 protein, mouse
• Enzyme Inhibitors
• Ionophores
• Membrane Proteins
• Proto-Oncogene Proteins
• Calcimycin
• Hydrogen Peroxide
• Caspase 9
• Staurosporine

Topics

• Animals
• Apoptosis Regulatory Proteins (deficiency, metabolism)
• Bcl-2-Like Protein 11
• Calcimycin (pharmacology)
• Caspase 9 (metabolism)
• Cell Death (drug effects, genetics, physiology)
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Developmental (drug effects, physiology)
• Hydrogen Peroxide (pharmacology)
• In Situ Nick-End Labeling (methods)
• Ionophores (pharmacology)
• Membrane Proteins (deficiency, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Mutant Strains
• Proto-Oncogene Proteins (deficiency, metabolism)
• Retina (cytology, growth & development)
• Retinal Degeneration (metabolism)
• Staurosporine (pharmacology)