CYTOKINE REGULATION OF NEURONAL GENE EXPRESSION

LIF/CNTF家族神经生成细胞因子对神经元的影响 分化、存活和对损伤的反应 这些蛋白质产生这些效应的机制尚不清楚。 他们的传出神经干在活体内或通过 体外培养的交感神经元经历LIF依赖的坐标 神经肽合成增加。这似乎是 神经细胞对损伤的反应，类似于 大鼠交感神经细胞分化反应的实验研究 LIF治疗。这个基因组计划所依据的核机制 LIF激活交感神经元中协调基因的激活 轴突切断后在体内和体外的情况尚不清楚。作为计划的一部分 培养的交感神经细胞的分化反应 交感神经切断后在体内，Stat转录因子是 被LIF激活，与反应细胞因子的区域相互作用 VIP基因内的元素(CyRE)。在其他细胞类型中，Stat蛋白 激活伴随着JAK受体家族的磷酸化 相关的酪氨酸激酶。我们假设JAK的激活- STAT通路是LIF核分化信号的一部分 神经节后神经肽基因的协调调节 轴突切断术。我们建议表征Jak-Stat通路在 LIF对上位神经肽基因表达的调节作用 内源性LIF释放时的颈神经节(SCG) (体外培养和体内轴突切断)。我们将使用LIF“基因敲除”小鼠 评估LIF作为激活JAK-STATE的内源性信号的作用 体内轴突切断后和体外器官培养后的信号通路。 更广泛地说，这些研究将确定这种新的 一类公认的神经生成性细胞因子将信号传导到 易感神经元细胞核对神经元的影响 分化和对伤害的反应。

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.