The Invulnerability of Adult Neurons: A Critical Role for p73

Abstract

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 p73ϩ/Ϫ mice. Adult p73ϩ/Ϫ DRG neurons were more vulnerable to apoptotic stimuli than their p73ϩ/ϩ counterparts, and invulnerability could be restored to the p73ϩ/Ϫ neurons by increased expression of ⌬Np73. Moreover, although DRG neuron development was normal in p73ϩ/Ϫ animals in vivo, axotomy caused death of adult p73ϩ/Ϫ but not p73ϩ/ϩ 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.

p63 Antagonizes p53 to Promote the Survival of Embryonic Neural Precursor Cells

“…Interestingly, the finding that adult SVZ stem cells from p53 Ϫ/Ϫ mice display enhanced proliferation and reduced apoptosis (Meletis et al, 2006) suggests that this may be a role that ⌬Np63 and p53 continue to play in neural precursors throughout their lifetime. Our data showing that ⌬Np73 is important for the survival of newly born cortical neurons, but not for cortical precursors, confirms previous work emphasizing the importance of this protein for neuronal survival (Pozniak et al, 2000(Pozniak et al, , 2002Walsh et al, 2004;Wetzel et al, 2008). In this regard, although our data indicate that ⌬Np63 collaborates with ⌬Np73 to promote survival of newly born cortical neurons, it is still unclear whether ⌬Np63 is important throughout a neuron's lifetime, as is ⌬Np73, or whether it only supports survival during the transition from a precursor to a postmitotic neuron.…”

“…One such central, integrative pathway in both central and peripheral neurons involves the p53 family (for review, see Jacobs et al, 2006;Miller and Kaplan, 2007). In particular, ⌬Np73 functions as a major neuronal survival and maintenance protein (Pozniak et al, 2000(Pozniak et al, , 2002Walsh et al, 2004), a function it fulfills at least partially by antagonizing full-length isoforms of p53 (Aloyz et al, 1998;Pozniak et al, 2000;Lee et al, 2004) and p63 (Jacobs et al, 2005). The importance of ⌬Np73 has recently been emphasized by the finding that p73 haploinsufficiency leads to neuronal degeneration and accumulation of aberrantly phosphorylated tau in the brains of aging and Alzheimer's disease model mice (Wetzel et al, 2008), phenotypes that are at least partially caused by dysregulation of JNK activity (Lee et al, 2004;Wetzel et al, 2008).…”

A novel role for jun N-terminal Kinase signaling in olfactory sensory neuronal death

“…This source of regulation, while commonly occurring in developmental death, and in adult death in disease models, has not been observed previously in ongoing neuronal death within healthy adult tissue (Repici and Borsello, 2006). In fact, in dorsal root ganglia sensory neurons, although the JNK pathway is induced by apoptotic stimuli in both developing and adult neuronal cultures, only neonatal cultures are susceptible to death by c-jun phosphorylation; adult neurons are protected downstream of JNK activity (Walsh et al, 2004). Thus it appears that JNK signaling in non-pathological, adult, neuronal death is unique to OSNs.…”

ΔNp73 Modulates Nerve Growth Factor-Mediated Neuronal Differentiation through Repression of TrkA

“…Moreover, overexpression of ⌬Np73 promotes immortalization in primary cells and malignant transformation in NIH 3T3 fibroblasts (35,43). In addition to its oncogenic potential, ⌬Np73 plays a crucial role in neuronal survival through both p53-dependent and -independent mechanisms (29,36,37,48). The underlying mechanism of these biological phenomena has been hypothesized as follows: ⌬Np73, by forming a heterotetramer with TAp73 or competing with TAp73 or p53 to bind to the p53-responsive element (p53-RE), antagonizes TAp73 or p53 since it was thought not to contain an activation domain.…”