Developing postmitotic mammalian neurons in vivo lacking Apaf-1 undergo programmed cell death by a caspase-independent, nonapoptotic pathway involving autophagy.
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.
Oppenheim
Ronald W
RW
Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. roppenhm@wfubmc.edu
Blomgren
Klas
K
Ethell
Douglas W
DW
Koike
Masato
M
Komatsu
Masaaki
M
Prevette
David
D
Roth
Kevin A
KA
Uchiyama
Yasuo
Y
Vinsant
Sharon
S
Zhu
Changlian
C
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D053477:Apoptotic Protease-Activating Factor 1 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D001343:Autophagy / Q000235:genetics; D020169:Caspases / Q000502:physiology*; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics
C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D020169:Caspases