SIGNALLING WITHIN THE DROSOPHILA SEGMENTAL NERVE

描述：（改编自申请人摘要） 神经系统的正常功能需要特定的相互作用， 神经元和神经胶质，然而这些相互作用的精确机制 发生仍然不完全理解。果蝇的节段神经， 包括一层运动和感觉轴突， （外周）和外（神经周）胶质层，提供了一个遗传系统， 对这种细胞间信号的分析。push基因的突变 在PI的实验室中鉴定和克隆的，以及Nf 1，果蝇的同源物， 基因负责人类神经纤维瘤病，每增加厚度 神经周围胶质层此外，推和Nf 1的效果 突变是强烈增强的突变，在ine编码一个 神经递质转运体Push突变在神经周围胶质细胞中的作用 编码钾通道的eag突变也能增强生长 亚单位push和Nf 1都编码细胞间信号传导的中间产物。 由PACAP神经肽介导的信号通路，或由amn编码的 蛋白质，与PACAP有关。因此，他们的结果与模型一致 其中果蝇的神经周围生长是由两个相互作用的 神经递质介导的信号通路，一个由Amn控制， 第二种是由底物神经递质控制的 通过eag来行动。PI建议进一步剖析这些 细胞间信号通路。提出了三个具体问题。首先是 Amn信号由周围胶质细胞释放并被神经周围胶质细胞接收， 是从神经元释放的信号，被外周神经胶质细胞接收， 通过中继机制传递给神经周围胶质细胞第二，Eag 钾通道作用于Amn信号细胞或Amn受体细胞， 调节Amn信号对神经生长的影响？第三，在其他 PACAP或Amn信号传导途径，已经描述了另外的中间体。 包括PKA、Ras和Raf。这些中间体中 参与果蝇节段神经中的Amn信号传导？这些 实验将为神经元/神经胶质的性质提供新的分子见解 信号此外，这一通路的信号缺陷似乎 模型，至少部分，发生在神经纤维瘤病的肿瘤形成。 因此，这里提出的研究预计将能够开发新的 Nf 1在肿瘤形成中的作用的模型，并可能使 开发新的药理学策略。

DESCRIPTION: (adapted from applicant's abstract) Proper function of the nervous system requires specific interactions between neurons and glia, and yet the precise mechanisms by which these interactions occur remain incompletely understood. The Drosophila segmental nerve, which comprises a layer of motor and sensory axons surrounded by an inner (peripheral) and outer (perineural) glial layer, provides a genetic system for the analysis of this intercellular signaling. Mutations in push, a gene identified and cloned in the PI's lab, and Nf1, the Drosophila homolog of the gene responsible for neurofibromatosis in humans, each increase the thickness of the perineural glial layer. In addition, the effect of push and Nf1 mutations are strongly potentiated by mutations in ine which encodes a neurotransmitter transporter. The effect of push mutations in perineural glial growth is also enhanced by mutations in eag which encodes a potassium channel subunit. Both push and Nf1 encode intermediates in the receipt of intercellular signaling pathways mediated by the PACAP neuropeptide, or by the amn-encoded protein, which is PACAP-related. Thus their results are consistent with a model in which perineural growth in Drosophila is controlled by two interacting neurotransmitter-mediated signaling pathways, one controlled by Amn and acting through push and Nf1, and the second controlled by substrate neurotransmitter of ine and acting through eag. The PI proposes a further dissection of these intercellular signaling pathways. Three specific questions are asked. First, is the Amn signal released from peripheral glia and received by perineural glia or is the signal released from neurons, received by peripheral glia and then signaled by a relay mechanism to perineural glia? Second, does the Eag potassium channel act in the Amn signaling cell, or in the Amn receiving cell, to modulate the effect of Amn signaling on perineural growth? Third, in other PACAP or Amn signaling pathways described, additional intermediates have been implicated, including PKA, Ras and Raf. Which of these intermediates participate in Amn signaling in the Drosophila segmental nerve? These experiments will provide new molecular insights into the nature of neuron/glia signaling. In addition, it appears that defects in signaling with this pathway models, at least in part, the tumor formation that occurs in neurofibromatosis. Thus the studies proposed here are anticipated to enable the development of new models for the role of Nf1 in tumor formation, and perhaps enable the development of new pharmacological strategies.