CYTOKINE REGULATION OF NEURONAL GENE EXPRESSION

LIF/CNTF家族的神经细胞因子影响神经细胞的生长， 分化，存活和对损伤的反应，但分子 这些蛋白质产生这些作用的机制尚不清楚。 当它们的传出神经干在体内或通过 在体外培养的交感神经元中， 神经肽合成增加。 这似乎是一个组成部分， 神经细胞对损伤的反应，类似于 培养的交感神经元的分化反应 LIF治疗。 这个基因组程序的核机制 LIF激活交感神经元中的协调基因激活 在体内和体外的轴突切开术后是未知的。 的一部分 在培养的交感神经元中的分化反应， 交感神经元轴突切断后，在体内，Stat转录因子， 由LIF激活以与细胞因子应答区域相互作用 VIP基因中的CyRE元件。 在其他细胞类型中，Stat蛋白 激活伴随着受体的Jak家族的磷酸化 相关的酪氨酸激酶。 我们假设激活了Jak- Stat途径是核“分化信号”的一部分， 产生协调调节神经肽基因后节后 轴突切断术 我们建议描述Jak-Stat途径在以下方面的作用： 上级神经肽基因表达的LIF依赖性调节 在内源性LIF释放的情况下，颈神经节（SCG） （体外培养和体内轴突切断）。 我们将使用LIF“敲除”小鼠 评估LIF作为激活Jak-Stat的内源性信号的作用， 在体内轴突切断后和在体外器官培养后的信号通路。 更一般地说，这些研究将确定机制， 公认的一类神经细胞因子将信号转导到 易感神经元细胞核影响神经元 分化和对损伤的反应。

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.