Activation of an apoptotic program in the central nervous system has different consequences depending on the specific context. Whereas apoptosis is essential for proper embryonic nervous system development, cell death occurring following neuronal injury and in neurodegenerative disease in adults has detrimental consequences. The p53 tumor suppressor is a regulator of cell death known to play a role both in proper neural tube closure and in apoptosis in neuronal diseases. To better understand the mechanism of p53- induced apoptosis, we performed a screen for target genes activated by p53 selectively during cell death, and we identified the pro-apoptotic gene Siva. We have shown that Siva is both sufficient to induce cell death and necessary for DNA-damage-induced, p53-dependent apoptosis in cultured neurons. Moreover, preliminary results indicate that Siva null mice we generated display embryonic lethality accompanied by neural tube closure defects. The overall goal of this project is to better define both 1) Siva's role in nervous system development and 2) Siva's mechanism of action in neuronal cell death. To understand Siva's developmental function in neural tube closure and brain development, we will perform a detailed analysis of Siva expression during embryogenesis coupled with a careful morphological and histological examination of the phenotypes associated with Siva-deficiency. The molecular basis of the defects observed upon Siva loss will be investigated by examining apoptosis, proliferation and differentiation markers. To elucidate the mechanism of action of Siva in apoptosis, we will characterize those features of apoptosis induced by Siva expression in neurons, and define components of the apoptotic machinery essential for Siva-induced cell death. Given the role of p53-dependent apoptosis in neuronal disease, Siva may contribute to human neurological disorders characterized by neuronal loss, either after acute neuronal injury, such as following ischemic stroke and traumatic brain injury, or in chronic diseases of neuronal loss, including Alzheimer's, Parkinson's, and Huntington's. Thus, our analyses of Siva will provide insight into congenital nervous system disorders and adult neuronal diseases and Siva may represent a promising therapeutic target for treating diseases characterized by excessive neuronal cell death. Apoptosis is a form of cellular suicide that plays an important part in sculpting the embryonic nervous system during development, but has detrimental consequences following neuronal injury and in neurodegenerative disease in adults. Our analyses of the gene Siva, a potent inducer of cell death in neurons, will provide insight into both congenital nervous system disorders and adult neuronal diseases. Moreover, because of its role in neuronal apoptosis, Siva represents a promising therapeutic target for treating diseases characterized by excessive neuronal cell death. ? ? ?
