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The Journal of Neuroscience, February 6, 2008, 28(6):1490-1497; doi:10.1523/JNEUROSCI.4575-07.2008

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Brief Communications
Developing Postmitotic Mammalian Neurons In Vivo Lacking Apaf-1 Undergo Programmed Cell Death by a Caspase-Independent, Nonapoptotic Pathway Involving Autophagy

Ronald W. Oppenheim,¹ Klas Blomgren,² Douglas W. Ethell,³ Masato Koike,⁴ Masaaki Komatsu,⁵ David Prevette,¹ Kevin A. Roth,⁶ Yasuo Uchiyama,⁴ Sharon Vinsant,¹ and Changlian Zhu²

¹Department of Neurobiology and Anatomy and the Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, ²Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Göteborg University, and Department of Pediatric Oncology, The Queen Silvia Children's Hospital, SE 40530 Göteborg, Sweden, ³Department of Biomedical Sciences, University of California, Riverside, California 92521, ⁴Department of Cell Biology and Neuroscience, Osaka University, Osaka 565-0871, Japan, ⁵Department of Biochemistry, Juntendo University, Tokyo 113-8421, Japan, and ⁶Department of Pathology, University of Alabama, Birmingham, Alabama 35294

Correspondence should be addressed to Ronald W. Oppenheim at the above address. Email: roppenhm{at}wfubmc.edu

Previous studies have shown that caspases and Apaf-1 are required for the normal programmed cell death (PCD) in vivo of immature postmitotic neurons and mitotically active neuronal precursor cells. In contrast, caspase activity is not necessary for the normal PCD of more mature postmitotic neurons that are establishing synaptic connections. Although normally these cells use caspases for PCD, in the absence of caspase activity these neurons undergo a distinct nonapoptotic type of degeneration. We examined the survival of these more mature postmitotic neuronal populations in mice in which Apaf-1 has been genetically deleted and find that they exhibit quantitatively normal PCD of developing postmitotic neurons. We next characterized the morphological mode of PCD in these mice and show that the neurons degenerate by a caspase-independent, nonapoptotic pathway that involves autophagy. However, autophagy does not appear to be involved in the normal PCD of postmitotic neurons in which caspases and Apaf-1 are present and functional because quantitatively normal neuronal PCD occurred in the absence of a key gene required for autophagy (ATG7). Finally, we examined the possible role of another caspase-independent type of neuronal PCD involving the apoptosis-inducing factor (AIF). Mice deficient in AIF also exhibit quantitatively normal PCD of postmitotic neurons after caspase inhibition. Together, these data indicate that, when key components of the type 1 apoptotic pathway (i.e., caspases and Apaf-1) are perturbed in vivo, developing postmitotic neurons nonetheless undergo quantitatively normal PCD by a caspase-independent pathway involving autophagy and not requiring AIF.

Key words: neuron; cell death; mouse; Apaf-1; autophagy; AIF; ATG7

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Received Oct. 8, 2007; revised Dec. 6, 2007; accepted Dec. 10, 2007.

Correspondence should be addressed to Ronald W. Oppenheim at the above address. Email: roppenhm{at}wfubmc.edu

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