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J. Biol. Chem., Vol. 278, Issue 43, 41938-41946, October 24, 2003

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Alternative Programs of Cell Death in Developing Retinal Tissue^*

Cinthya A. Guimarães, Marlene Benchimol¶, Gustavo P. Amarante-Mendes||**, and Rafael Linden

From the Instituto de Biofísica, Universidade Federal do Rio de Janeiro, 21949-900 Rio de Janeiro, the ^¶Universidade Santa Úrsula, Rio de Janeiro, and the ^||Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo and Instituto de Investigação em Imunologia, Instituto do Milênio, Brazil

We examined cell death in developing retinal tissue, following inhibition of protein synthesis, which kills undifferentiated post-mitotic cells. Ultrastructural features were found of both apoptosis and autophagy. Only approximately half of the degenerating cells were either terminal dUTP nick-end labeling (TUNEL)-positive or reacted with antibodies specific for activated caspases-3 or -9. Bongkrekic acid completely inhibited any appearance of cell death, whereas inhibitors of autophagy, caspases-9 or -3, prevented only TUNEL-positive cell death. Interestingly, inhibition of caspase-6 blocked TUNEL-negative cell death. Simultaneous inhibition of caspases-9 and -6 prevented cell death almost completely, but degeneration dependent on autophagy/caspase-9 still occurred under inhibition of both caspases-3 and -6. Thus, inhibition of protein synthesis induces in the developing retina various post-translational, mitochondria-dependent pathways of cell death. Autophagy precedes sequential activation of caspases-9 and -3, and DNA fragmentation, whereas, in parallel, caspase-6 leads to a TUNEL-negative form of cell death. Additional mechanisms of cell death may be engaged upon selective caspase inhibition.

Received for publication, June 20, 2003 , and in revised form, August 5, 2003.

^* This work was supported in part by grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, FAPERJ, and PRONEXMCT. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Biological Chemistry, Inst. of Life Sciences, Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel.

^** Member of the Instituto do Milênio de Investigação em Imunologia.

Fellow of the John Simon Guggenheim Foundation. To whom correspondence should be addressed: Instituto de Biofísica da Universidade Federal do Rio de Janeiro, CCS, bloco G, Cidade Universitária, 21949-900 Rio de Janeiro, Brazil. Tel.: 55-21-25626553; Fax: 55-21-2280-8193; E-mail: rlinden{at}biof.ufrj.br.

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