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The Journal of Neuroscience, October 13, 2004, 24(41):9174-9184; doi:10.1523/JNEUROSCI.1588-04.2004

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Cellular/Molecular
Evidence That Np73 Promotes Neuronal Survival by p53-Dependent and p53-Independent Mechanisms

Anna F. Lee,^1,2,5 Daniel K. Ho,^1,2,5 Patrizia Zanassi,^1,2 Gregory S. Walsh,^1,2,5 David R. Kaplan,^1,2,3 and Freda D. Miller^1,2,3,4

Departments of ¹Developmental Biology and ²Cancer Research, Hospital for Sick Children, Departments of ³Molecular and Medical Genetics and ⁴Physiology, University of Toronto, Toronto, Ontario, M5G 1X8 Canada, and ⁵Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3A 2B4 Canada

The p53 family member, p73, is essential for the survival of sympathetic neurons during the developmental period of naturally occurring neuronal death. Here, we have asked whether Np73, which is the only p73 isoform expressed in sympathetic neurons, mediates this survival by p53-dependent and/or p53-independent mechanisms. Initially, we used a genetic approach and crossed p53^+/- and p73^+/- mice. Quantitation of neurons in the sympathetic superior cervical ganglion during the period of naturally occurring cell death revealed that the loss of p53 partially rescued the death of neurons seen in p73^-/- animals. Moreover, exogenous expression of Np73 in cultured p53^-/- sympathetic neurons rescued these neurons from apoptosis after NGF withdrawal. Biochemical studies asking how Np73 inhibited NGF withdrawal-induced apoptosis in wild-type neurons demonstrated that it prevented the upregulation of the direct p53 targets p21 and Apaf-1 as well as cleavage of caspase-3. It also inhibited events at the mitochondrial apoptotic checkpoint, suppressing the induction of BimEL and the release of mitochondrial cytochrome c. Interestingly, Np73 expression also inhibited one very early event in the apoptotic cascade, the activation of c-Jun N-terminal protein kinase (JNK), likely by binding directly to JNK. Finally, we show that neuronal cell size is decreased in p73^-/- mice, and that this decrease is not rescued by the lack of p53, suggesting a role for p73 in regulating cell size that does not involve interactions with p53. Thus, Np73 promotes neuronal survival via p53-dependent and -independent mechanisms, and it does so at multiple points, including some of the most proximal events that occur after NGF withdrawal.

Key words: nerve growth factor; sympathetic neurons; Apaf-1; cytochrome c; JNK; Bim; cell size

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Received April 26, 2004; revised August 20, 2004; accepted September 3, 2004.

This article has been cited by other articles:

				C. B. Dugani, A. Paquin, M. Fujitani, D. R. Kaplan, and F. D. Miller p63 Antagonizes p53 to Promote the Survival of Embryonic Neural Precursor Cells J. Neurosci., May 20, 2009; 29(20): 6710 - 6721. [Abstract] [Full Text] [PDF]

				W. H. Toh, E. Logette, L. Corcos, and K. Sabapathy TAp73{beta} and DNp73{beta} activate the expression of the pro-survival caspase-2S Nucleic Acids Res., August 1, 2008; 36(13): 4498 - 4509. [Abstract] [Full Text] [PDF]

				J. Zhang and X. Chen {Delta}Np73 Modulates Nerve Growth Factor-Mediated Neuronal Differentiation through Repression of TrkA Mol. Cell. Biol., May 15, 2007; 27(10): 3868 - 3880. [Abstract] [Full Text] [PDF]

				S. Naska, K. J. Park, G. E. Hannigan, S. Dedhar, F. D. Miller, and D. R. Kaplan An Essential Role for the Integrin-Linked Kinase-Glycogen Synthase Kinase-3{beta} Pathway during Dendrite Initiation and Growth J. Neurosci., December 20, 2006; 26(51): 13344 - 13356. [Abstract] [Full Text] [PDF]

				G. S. Walsh, N. Orike, D. R. Kaplan, and F. D. Miller The Invulnerability of Adult Neurons: A Critical Role for p73 J. Neurosci., October 27, 2004; 24(43): 9638 - 9647. [Abstract] [Full Text] [PDF]

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