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The Journal of Neuroscience, October 27, 2004, 24(43):9638-9647; doi:10.1523/JNEUROSCI.1299-04.2004

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Cellular/Molecular
The Invulnerability of Adult Neurons: A Critical Role for p73

Gregory S. Walsh,^1,2 * Nina Orike,^2 * David R. Kaplan,^1,2 and Freda D. Miller^1,2

¹Developmental Biology and Cancer Research, Hospital for Sick Children, Departments of Medical Genetics and Physiology, University of Toronto, Toronto, Ontario, Canada M5G 1X8, and ²Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4

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, Np73, 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 Np73. 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.

Key words: p73; p53 tumor suppressor; sensory neurons; dorsal root ganglion; sciatic nerve injury; nerve growth factor; neuronal apoptosis; JNK; PI3-kinase; DNA damage

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Received April 6, 2004; revised September 1, 2004; accepted September 14, 2004.

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