Motoneuron resistance to apoptotic cell death in vivo correlates with the ratio between X-linked inhibitor of apoptosis proteins (XIAPs) and its inhibitor, XIAP-associated factor 1.
Apoptotic cell death occurs in motoneurons in the neonate but not in the adult after a lesion of a peripheral nerve. To investigate the molecular basis for this difference, we have analyzed the expression and localization of inhibitors of apoptosis proteins (IAPs) and their inhibitors X-linked IAP (XIAP)-associated factor 1 (XAF1), Smac/DIABLO, and Omi/HtrA2 in motoneurons at both ages. Quantitative immunohistochemical and immunoblotting analysis of these proteins in motoneurons revealed an increase in IAP expression [XIAP, neuronal apoptosis inhibitory protein, human IAP1 (HIAP1), and HIAP2] during postnatal development as opposed to XAF1, which decreased during the same period; there was no significant alteration in either Smac/DIABO or Omi/HtrA2. The regulation of IAPs and XAF1 varied after axotomy of the sciatic nerve; in the neonate, there was a significant loss of IAP in the injured motoneurons as opposed to the adult, in which there was only a moderate decrease. By overexpressing exogenous IAPs in neonatal axotomized motoneurons, it was possible to delay motoneuron cell death (Perrelet et al., 2000, 2002). In opposition, the overexpression of exogenous XAF1 in adult motoneurons totally abrogated the natural resistance of these cells to axotomy. The degradation in the adult, induced by XAF1, could be overcome by simultaneously expressing high levels of exogenous XIAP in adult motoneurons. These experiments suggest that it may be the ratio between XAF1 and XIAP that confers the resistance of adult motoneurons to axotomy. In addition, the regulation in the levels of IAPs and XAF1 may be essential in the cell death mechanism of injured motoneurons.
Perrelet
Daniel
D
Division of Clinical Neuromuscular Research and Department of Anesthésiologie, Pharmacologie et Soins Intensifs de Chirurgie, Faculty of Medicine, Centre Médical Universitaire, 1211 Geneva 4, Switzerland.
Perrin
Florence E
FE
Liston
Peter
P
Korneluk
Robert G
RG
MacKenzie
Alex
A
Ferrer-Alcon
Marcel
M
Kato
Ann C
AC
D048868:Adaptor Proteins, Signal Transducing; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D019771:Axotomy; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D002470:Cell Survival / Q000502:physiology; D005456:Fluorescent Dyes; D018014:Gene Transfer Techniques; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins; D008161:Lumbosacral Region; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D051616:Neuronal Apoptosis-Inhibitory Protein; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000378:metabolism* / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013266:Stilbamidines; D051636:X-Linked Inhibitor of Apoptosis Protein
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C412403:DIABLO protein, human; C489013:DIABLO protein, rat; D005456:Fluorescent Dyes; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C496800:NAIP protein, human; C496803:Naip6 protein, rat; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D051616:Neuronal Apoptosis-Inhibitory Protein; D011506:Proteins; D013266:Stilbamidines; D051636:X-Linked Inhibitor of Apoptosis Protein; C417551:XAF1 protein, human; C496866:XIAP protein, human; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2