Nervous system development is characterized by extensive cell death. Approximately 50 percent of neurons die in the developing brain, in part due to competition for target-derived neurotrophic molecules. Although not as extensively investigated, neuronal cell death also occurs prior to synaptogenesis and the acquisition of neurotrophic factor dependency.Neuronal progenitors and/or early post-mitotic neurons exhibit significant cell death in the brain, spinal cord, and dorsal root ganglia. We have shown that the susceptibility of immature, postmitotic neurons to death is greatly exacerbated in mice lacking bcl-x, a member of the bcl-2 gene family. In vitro studies indicate that bcl-x immature deficient neurons, similar to bcl-x-deficient immature lymphocytes, are markedly susceptible to apoptosis. In the immune system, immature lymphocytes are destined to die unless they express specific cell surface molecules that permit positive selection. We hypothesize that a similar selection process occurs in the nervous system and may relate to the development of regional identity. The goals of this proposal are to test the hypothesis that neuronal selection occurs during nervous system development prior to synaptogenesis and neurotrophic factor dependency, and to determine the role of bcl-2 gene family in this process. The bcl-2 gene family consists of several molecules with either pro- or anti-apoptotic action whose coordinate expression and intracellular dimerization regulate cell viability. Bcl-2 and Bcl-xL are thought to prevent death by heterodimerization with pro-apoptotic bcl-2 family members including Bax, Bad, and Bak. Based on published reports and our own in situ hybridization results, bax is expressed at relatively high levels in the embryonic mouse brain. Both bad- and bax-deficient mice have been generated and we find increased neuron numbers in several discrete populations. We hypothesize that the coordinate regulation of bcl-2 gene family member expression during neuronal maturation may critically control neuronal selection. To accomplish our goals, we will determine the temporal and maturation dependence of neuronal expression patterns of bcl-2 related family members in the embryonic mouse brain, and examine the effects of bcl-x, bcl-2, bad, and bax deficiency on the survival of immature postmitotic neurons in vivo and in vitro. To test the hypothesis that selection of immature neurons is related to regional identity, in vivo and in vitro experiments designed to assess the relationship of neuronal apoptosis to the expression of regionally-specific markers will be performed. These experiments should yield significant new data on the role of the bcl-2 gene family in neuronal development and ultimately lead to the identification of the molecular signals that regulate immature neuron selection.
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