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首页> 外文学位 >Signaling mechanisms that control presynaptic morphogenesis at the Drosophila neuromuscular junction.
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Signaling mechanisms that control presynaptic morphogenesis at the Drosophila neuromuscular junction.

机译：控制果蝇神经肌肉连接处突触前形态发生的信号传导机制。

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摘要

The development of the pretsynaptic terminal requires the assembly of many adhesion, receptor, scaffold and signaling molecules. Previous work from our lab has focused on the relationship between the receptor tyrosine phosphatase LAR, the heparan sulfate proteoglycans Syndecan and Dallylike and the scaffold protein Liprin-alpha in promoting presynaptic differentiation. In this current study, we expand this work to identify downstream effectors known for their direct interaction with actin cytoskeleton. Thus, we define the LAR signaling pathway that links cell surface cues at the presynaptic terminal to actin cytoskeleton during presynaptic development.;LAR and Syndecan binding occurs at the cell surface. Liprin-alpha localizes to the synaptic terminal through its cytoplasmic interaction with LAR. However, the functional relationship between the three molecules LAR, Syndecan and Liprin-alpha has never been explored. We demonstrate that LAR, Syndecan and Liprin-alpha depend on each other for activity and, thus, each serves as a limiting factor during presynaptic differentiation. While a hierarchical relationship between the three molecules was not established genetically, these results are indicative of a complex. Liprin-alpha has been linked to multiple proteins necessary for presynaptic differentiation. However, at the presynaptic terminal LAR cytoplasmic interactions are limited to the Liprin-alpha partnership. To expand the LAR signaling pathway, we focused on two LAR substrates as possible downstream effectors: the Abelson tyrosine kinase and Enabled.;The importance of actin remodeling during presynaptic differentiation has been demonstrated through pharmacological applications. Interestingly, both Abelson (Abl) tyrosine kinase and Enabled proteins are characterized by their association with cytoskeleton structure. We use genetics and microscopy to demonstrate Abl requirement for presynaptic growth and establish Abl as a modulator of active zone assembly. Further, we show that Abl function is required for LAR, Syndecan and Liprin-alpha activity, placing Abl downstream of these molecules. Enabled is a substrate of both LAR and Abl. We establish a role for Enabled in both synaptic growth and active zone assembly. Further, epistasis reveals the requirement for Enabled activity in the LAR pathway, placing Enabled function downstream of LAR, Syndecan and Liprin-alpha. Taken together, the LAR signal transduction pathway functions to modulate actin dynamics necessary for proper synaptic development.
机译：突触前终末的发展需要许多粘附，受体，支架和信号分子的组装。我们实验室先前的工作集中在受体酪氨酸磷酸酶LAR，硫酸乙酰肝素蛋白聚糖Syndecan和Dallylike与支架蛋白Liprin-alpha在促进突触前分化之间的关系上。在当前的研究中，我们扩展了这项工作，以鉴定以其与肌动蛋白细胞骨架的直接相互作用而闻名的下游效应子。因此，我们定义了在突触前发育过程中将突触前末端细胞表面线索连接至肌动蛋白细胞骨架的LAR信号通路。LAR和Syndecan结合发生在细胞表面。脂蛋白-α通过与LAR的胞质相互作用而定位于突触末端。然而，从未探索过三个分子LAR，Syndecan和Liprin-alpha之间的功能关系。我们证明了LAR，Syndecan和Liprin-α彼此依赖于活性，因此，它们在突触前分化过程中均起限制作用。虽然这三个分子之间没有层次关系，但这些结果表明存在复杂性。脂蛋白-α已与突触前分化所必需的多种蛋白质相连。但是，在突触前末端，LAR的胞质相互作用仅限于Liprin-alpha伙伴关系。为了扩展LAR信号传导途径，我们集中于两个LAR底物作为可能的下游效应子：Abelson酪氨酸激酶和Enabled。;通过药理学应用已证明了肌动蛋白重塑在突触前分化过程中的重要性。有趣的是，Abelson（Abl）酪氨酸激酶和Enabled蛋白均以其与细胞骨架结构的关联为特征。我们使用遗传学和显微镜来证明Abl对突触前生长的要求，并建立Abl作为活性区装配的调节剂。此外，我们显示Abl功能是LAR，Syndecan和Liprin-alpha活性所必需的，将Abl置于这些分子的下游。启用了LAR和Abl的底物。我们为Enabled在突触生长和活动区域装配中发挥作用。此外，上位性揭示了LAR途径需要Enabled活性，从而将Enabled功能置于LAR，Syndecan和Liprin-alpha的下游。综上所述，LAR信号转导途径的功能是调节突触发育所需的肌动蛋白动力学。

著录项

  • 作者

    Thompson, Cheryl Lynn.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Biology Neuroscience.;Biology Cell.;Biology Genetics.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 270 p.
  • 总页数 270
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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