The role of BCL-2 protein family in the development of the peripheral nervous system
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The aim of this study was to ascertain the roles of selected members of the bcl-2 protein family of proteins in the developing peripheral nervous system. Two experimental approaches were used: microinjection of expression plasmids encoding these proteins into cultured neurons and studying the in vitro and in vivo development of neurons in mouse embryos with targeted null mutations in the genes encoding these proteins. Overexpression of bcl-2, bcl-xL, and bcl-xbeta in cultured embryonic sensory neurons prevented the death of these neurons following neurotrophin withdrawal. Accordingly, sensory neurons from bcl-2-l- embryos survived less well in culture with neurotrophins than neurons from wild type embryos and there were fewer neurons and more dying cells in the cranial sensory ganglia of bcl-2-l- embryos during the phase of naturally occurring neuronal death. In addition to demonstrating a role for bcl-2 in regulating the survival of embyronic sensory neurons, studies of neurons from of bcl-2-l- embryos revealed new roles for bcl-2 in neuronal development, bcl-2-deficient sensory neurons extended axons more slowly and underwent an early maturational change more slowly than wild type neurons, indicating that bcl-2 may regulate aspects of early neuronal development independently of its effects on survival. Overexpression of bax in chicken sensory neurons also rescued some of these neurons following neurotrophin deprivation, contradicting the view that bax is exclusively a pro-apoptotic member of the bcl-2 family. However, sensory neurons from bax-2-l- embryos survived better in culture than neurons from wild type embryos and there were more neurons and fewer dying cells in the cranial sensory ganglia of bax-2-l- embryos, suggesting that bax may play different roles in regulating the survival of certain neurons in these two classes of vertebrates.
Thesis, PhD Doctor of Philosophy
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