SIGNALLING WITHIN THE DROSOPHILA SEGMENTAL NERVE

描述：(改编自申请者摘要) 神经系统的正常功能需要 神经元和神经胶质细胞，以及这些相互作用的确切机制 发生的情况仍未完全弄清楚。果蝇节段性神经，它 包括一层运动和感觉轴突，周围环绕着一个内部 (外周)和外(神经)神经胶质层，提供了一种遗传系统 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了Nf1，果蝇的同源物Nf1 导致人类神经纤维瘤病的基因，每个基因都会增加厚度 神经周围神经胶质层。此外，推送和NF1的影响 突变被编码a的ine的突变所强烈增强 神经递质转运体。Push突变对神经周围神经胶质细胞的影响 编码钾通道的EAG基因突变也促进了生长 亚单位。PUSH和NF1都编码细胞间信号的中间产物 PACAP神经肽或AMN编码的信号转导通路 蛋白质，它与PACAP相关。因此，他们的结果与模型是一致的 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，一条由AMN控制并起作用的通路 通过Push和Nf1，第二个由底物神经递质控制 通过EAG演戏。PI建议对这些进行进一步的剖析 细胞间信号通路。他们问了三个具体的问题。首先，是 AMN信号从周围神经胶质细胞释放出来，并由神经周围神经胶质细胞或 是神经元释放的信号，由外周神经胶质细胞接收，然后 由神经周围神经胶质细胞的中继机制发出的信号？第二，EAG 钾通道作用于AMN信令细胞，或作用于AMN接收细胞， 调节AMN信号对周围神经生长的影响？第三，在其他方面 PACAP或AMN信号通路已描述，其他中间体已被描述 涉案人员包括PKA、RAS和RAF。这些中间体中的哪一个 参与果蝇节段性神经的AMN信号传递？这些 实验将为神经元/神经胶质细胞的本质提供新的分子见解 发信号。此外，这一途径的信号传递缺陷似乎 模型，至少部分，发生在神经纤维瘤病的肿瘤形成。 因此，这里提出的研究有望使新的 NF1在肿瘤形成中的作用的模型，并可能使 开发新的药理策略。

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.