Programmed cell death (PCD), which results in apoptosis, occurs widely during neuronal development and is also observed in pathological situations of stroke, spinal cord injury, and neurodegenerative disease. The mechanism of neuronal PCD has been extensively studied in sympathetic neurons that undergo apoptosis after nerve growth factor (NGF) removal in culture. A critical factor regulating apoptosis in many cells is the cytochrome c-dependent activation of caspases. Although necessary in sympathetic neurons, cytochrome c release is not sufficient to induce apoptosis after NGF deprivation. We have recently demonstrated that a novel, uncharacterized event, called the """"""""development of competence,"""""""" is needed, along with cytosolic cytochrome c to induce caspase activation and apoptosis in these neurons. We shall examine whether the development of competence event is also important in other models of neuronal apoptosis and test the specific hypothesis that the requirement of development of competence to induce apoptosis is a phenomenon unique to postmitotic cells. We shall also examine the signaling pathway activated after NGF deprivation that leads to the development of competence. Since our preliminary results suggest that the c-jun-N-terminal kinase (JNK) signaling pathway is important in regulating competence in sympathetic neurons, we shall focus specifically on components of this signaling pathway. Lastly, we shall examine the molecular mechanism of development of competence. Our recent data suggest that competence may be controlled by an inhibitor of apoptosis protein (IAP) like activity. We shall examine this hypothesis and test the specific importance of Smac, a recently identified inhibitor of lAPs, in regulating the development of competence in neurons. These studies will provide an understanding of the biological importance and mechanism of development of competence in promoting neuronal apoptosis. Knowledge of this pathway may also identify targets for the development of strategies to suppress apoptosis and ameliorate the consequences of neuronal injury and neurodegenerative disease.
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