Author: Gregory S. WalshPublisher:
ISBN:
Category :
Languages : en
Pages : 332
Book Description
"Developmental sympathetic neuron death is determined by functional interactions between the TrkA/NGF receptor and the p75 neurotrophin receptor (p75NTR). A key question is whether p75NTR promotes apoptosis by directly inhibiting or modulating TrkA activity, or by stimulating cell death independently of TrkA. Here we show that the presence or absence of p75NTR does not alter Trk activity or NGF- and NT-3-mediated downstream survival signaling in primary neurons. Crosses of p75NTR-/- and TrkA-/-mice indicate that the coincident absence of p75NTR substantially rescues TrkA-/-sympathetic neurons from developmental death in vivo. These data support a model where developing sympathetic neurons are "destined to die" by an ongoing p75NTR-mediated apoptotic signal, and one of the major ways that TrkA promotes neuronal survival is by silencing this ongoing death signal. We then examined a role for JNK-p53 apoptotic pathway in NGF-deprived neurons and in nerve injury-induced death. Specifically, inhibition of JNK by overexpression of JIP-1 was sufficient to rescue sympathetic neurons from NGF withdrawal-induced death. In addition, JNK is robustly activated in nerve-injured neonatal facial motoneurons and these neurons are rescued from nerve-injury-induced cell death in p53 null mice. We then investigated the intracellular mechanisms that underlie the relative invulnerability of adult versus developing DRG sensory neurons. In both adult and neonatal neurons, death stimuli induced the apoptotic JNK pathway, but JNK activation only caused death of neonatal neurons, indicating that adult neurons have a downstream block to apoptosis. An essential component of this "block" is the p53 family member, DeltaNp73. Cultured 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" --