Embryonic neuronal death due to neurotrophin and neurotransmitter deprivation occurs independent of Apaf-1

Honarpour, Narimon; Tabuchi, Katsuhiko; Stark, James M.; Hammer, Robert E.; Südhof, Thomas C.; Parada, Luis F.; Wang, X.; Richardson, James A.; Herz, Joachim

doi:10.1016/s0306-4522(01)00275-5

Cited by 20 publications

(12 citation statements)

References 51 publications

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“…We now demonstrate for the first time in vivo that, after the genetic deletion of Apaf-1, several populations of postmitotic neurons in the central and peripheral nervous system undergo normal amounts of PCD and that the degeneration occurs by a morphological pathway distinct from that observed in the same neuronal populations in the presence of Apaf-1. These results differ from the observations of Honarpour et al (2001a) who report increased neuron numbers (i.e., reduced PCD) in the DRG and trigeminal ganglion of Apaf-1 KO mice on E16.5. Although the reason for the different results is not clear, it may be attributable to the small sample size (n ϭ 1 per group) and the apparent failure to do blinded cell counts.…”

Section: Discussioncontrasting

confidence: 99%

“…We previously reported that the extent of neuronal PCD during this later phase is unaffected by the genetic deletion of either caspase-3 or caspase-9 (Oppenheim et al, 2001a) and the PCD of postmitotic motor neurons (MNs) in the chick embryo has also been shown to be unaffected after the pharmacological inhibition of caspases (Yaginuma et al, 2001). In the present study, we examined PCD in several populations of target-dependent neurons in Apaf-1 knock-out (KO) mice, and contrary to a previous report (Honarpour et al, 2001a), we find that PCD occurs to the same extent as in wild-type (WT) control animals.…”

Section: Introductionmentioning

confidence: 79%

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Developing Postmitotic Mammalian NeuronsIn VivoLacking Apaf-1 Undergo Programmed Cell Death by a Caspase-Independent, Nonapoptotic Pathway Involving Autophagy

Oppenheim¹,

Blomgren²,

Ethell³

et al. 2008

J. Neurosci.

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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.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 79%

Developing Postmitotic Mammalian NeuronsIn VivoLacking Apaf-1 Undergo Programmed Cell Death by a Caspase-Independent, Nonapoptotic Pathway Involving Autophagy

Oppenheim¹,

Blomgren²,

Ethell³

et al. 2008

J. Neurosci.

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show abstract

“…Recent studies have shown, however, that their lymphocytes, myeloid cells and fibroblasts remain highly sensitive to cytotoxic conditions against which Bcl-2 protects (Marsden et al, 2002). Furthermore, some Apaf-1-null mice develop into healthy adults (Honarpour et al, 2000), Apaf-1 is not required for apoptosis of postmitotic neurons (Honarpour et al, 2001) or deletion of autoreactive thymocytes (Hara et al, 2002), and Bcl-2 can protect embryonic stem cells lacking Apaf-1 from stress-imposed death (Haraguchi et al, 2000). Thus, neither Apaf-1 nor caspase-9 is essential for stressinduced apoptosis.…”

Section: Pathways For Caspase Activationmentioning

confidence: 99%

The Bcl-2 family: roles in cell survival and oncogenesis

2003

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“…Moreover, in response to diverse insults against which Bcl-2 protects, lymphocytes lacking either Apaf-1 or caspase-9 died at near normal rates and with all the hallmarks of apoptosis. Indeed, even postmitotic neurons that lack Apaf-1 die normally (Honarpour et al 2001), and a few Apaf-1 −/− mice become healthy adults (Honarpour et al 2000).…”

Section: Amplification Role Of the Apoptosomementioning

confidence: 99%