SIGNALLING WITHIN THE DROSOPHILA SEGMENTAL NERVE

果蝇节段神经内的信号传导

基本信息

批准号：
6258690
负责人：
Michael J Stern
金额：
$ 25.29万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-08 至 2004-12-31
项目状态：
已结题

项目摘要

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.

描述：（改编自申请人的摘要）神经系统的正常功能需要神经系统之间的特定相互作用神经元和神经胶质细胞，以及这些相互作用的精确机制发生的情况仍不完全清楚。果蝇节段神经，包括一层运动和感觉轴突，周围有一个内部（外周）和外（神经周围）神经胶质层，提供了遗传系统分析这种细胞间信号传导。推动突变，基因在 PI 的实验室中鉴定并克隆了 Nf1，果蝇的同源物负责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胶质层。另外，push和Nf1的效果编码 a 的 ine 突变会强烈增强突变神经递质转运蛋白。神经周围胶质细胞推突变的影响编码钾通道的 eag 突变也会促进生长亚基。 Push 和 Nf1 都编码接收细胞间质的中间体由 PACAP 神经肽或 amn 编码的信号通路介导蛋白质，与 PACAP 相关。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控制的神经递质介导的信号通路，一种由 Amn 控制并发挥作用的通路通过push和Nf1，第二个由底物神经递质控制 ine 并通过 eag 进行操作。 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，是从周围神经胶质细胞释放并被神经周围神经胶质细胞接收的 Amn 信号或是从神经元释放的信号，由周围神经胶质细胞接收，然后通过神经周胶质细胞的中继机制发出信号？二、老鹰有没有钾通道在 Amn 信号细胞或 Amn 接收细胞中起作用，调节 Amn 信号对神经周围生长的影响？三、在其他方面描述了 PACAP 或 Amn 信号通路，其他中间体已牵涉其中的包括 PKA、Ras 和 Raf。其中哪些中间体参与果蝇节段神经的 Amn 信号传导？这些实验将为神经元/神经胶质细胞的性质提供新的分子见解发信号。此外，该途径的信号传导缺陷似乎至少部分地模拟神经纤维瘤病中发生的肿瘤形成。因此，这里提出的研究预计将能够开发新的 Nf1 在肿瘤形成中的作用模型，也许能够使开发新的药理学策略。