The invulnerability of adult neurons: a critical role for p73.
Here, we investigated the intracellular mechanisms that underlie the relative invulnerability of adult versus developing dorsal root ganglion (DRG) sensory neurons. In culture, adult neurons were resistant to stimuli that caused apoptosis of their neonatal counterparts. In both adult and neonatal neurons, death stimuli induced the apoptotic c-Jun N-terminal protein kinase (JNK) pathway, but JNK activation only caused death of neonatal neurons, indicating that adult neurons have a downstream block to apoptosis. Expression of the dominant-inhibitory p53 family member, DeltaNp73, rescued JNK-induced apoptosis of neonatal neurons, suggesting that it might participate in the downstream apoptotic block in adult neurons. To test this possibility, we examined adult DRG neurons cultured from p73+/- mice. Adult p73+/- DRG neurons were more vulnerable to apoptotic stimuli than their p73+/+ counterparts, and invulnerability could be restored to the p73+/- neurons by increased expression of DeltaNp73. Moreover, although DRG neuron development was normal in p73+/- animals in vivo, axotomy caused death of adult p73+/- but not p73+/+ DRG neurons. Thus, one way adult neurons become invulnerable is to enhance endogenous survival pathways, and one critical component of these survival pathways is p73.
Walsh
Gregory S
GS
Developmental Biology and Cancer Research, Hospital for Sick Children, Department of Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5G 1X8.
Orike
Nina
N
Kaplan
David R
DR
Miller
Freda D
FD
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D001369:Axons / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D005727:Ganglia, Spinal / Q000166:cytology; D016147:Genes, Tumor Suppressor; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009475:Neurons, Afferent / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D012584:Sciatic Nerve / Q000293:injuries; D017783:Superior Cervical Ganglion / Q000166:cytology; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D048031:JNK Mitogen-Activated Protein Kinases