CYTOKINE REGULATION OF NEURONAL GENE EXPRESSION

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The LIF/CNTF family of neuropoietic cytokines influences neuronal differentiation, survival and the response to injury but the molecular mechanisms by which these proteins produce these effects are not known. After their efferent nerve trunks have been severed in vivo or by culturing in vitro, sympathetic neurons undergo a LIF-dependent coordinate increase in neuropeptide synthesis. This appears to be a component of the response of the nerve cell to injury, and is similar to the differentiation response of cultured sympathetic neurons produced by treatment with LIF. The nuclear mechanisms by which this genomic program of coordinate gene activation in sympathetic neurons is activated by LIF after axotomy in vivo and in vitro are not known. As part of a differentiation response in cultured sympathetic neurons and in sympathetic neurons after axotomy in vivo, Stat transcription factors are activated by LIF to interact with a region of a cytokine responsive element (CyRE) within the VIP gene. In other cell types Stat protein activation is accompanied by phosphorylation of the Jak family of receptor associated tyrosine kinases. We hypothesize that activation of the Jak- Stat pathway is part of a nuclear "differentiation signal" by which LIF produces coordinate regulation of neuropeptide genes after postganglionic axotomy. We propose to characterize the role of the Jak-Stat pathway in LIF-dependent regulation of neuropeptide gene expression in the superior cervical ganglia (SCG) in situations where endogenous LIF is released (culturing in vitro and axotomy in vivo). We will use LIF "knockout" mice to assess the role of LIF as an endogenous signal activating the Jak-Stat signaling pathway after axotomy in vivo and after organ culture in vitro. More generally, these studies will identify mechanisms by which this newly recognized class of neuropoietic cytokines transduces signals to the nucleus of susceptible neuronal cells to influence neuronal differentiation and response to injury.