Cell Recognition in the developing Drosophila Brain

果蝇大脑发育中的细胞识别

基本信息

批准号：
8372389
负责人：
S. Lawrence Zipursky
金额：
$ 28.08万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-08 至 2013-11-30
项目状态：
已结题

项目摘要

Project Summary/Abstract The Drosophila Dscam gene encodes a vast family of immunoglobulin (Ig) superfamily proteins and plays a crucial role in regulating the formation of precisely organized neural circuits during development. Alternative splicing generates more than 38,016 different isoforms, including 19,008 ectodomains tethered to the membrane by one of two alternative transmembrane segments. These ectodomains share the same domain structure, but differ in amino acid sequence within three variable domains, Ig2, Ig3 and Ig7. Isoforms sharing the same combination of variable domains (i.e. they match at each variable domain) bind to each other, but they do not bind to other isoforms. Genetic analysis has revealed that Dscam plays a crucial role in a phenomenon called self-avoidance. Each neuron expresses a unique combination of isoforms and this allows its neurites to distinguish between self and non-self. Self-recognition, namely isoform-specific homophilic binding between neurites of the same cell, promotes repulsion between these processes. Self-avoidance plays an important role in the segregation of axon branches and the elaboration of dendritic fields and, thereby, contributes to the assembly of neural circuits. In this proposal, we will address three questions: 1. Is homophilic recognition crucial for all of Dscam's functions? To address this question we will generate knock-in mutants of Dscam which have lost the ability to engage in homophilic binding; 2. Are specific isoforms of Dscam expressed in distinct populations of neurons? While Dscam clearly plays a role in self-avoidance, it remains possible that different populations of neurons may use specific isoforms of Dscam to recognize other neurons. This aim is directed towards identifying such cells; and 3. Are their requirements in specific neurons for different alternative Ig domains? To address this question we will generate separate lines of flies with a single Ig2 domain, a single Ig3 domain or a single Ig7 domain. While Dscam diversity is not observed in mammals, Dscam is expressed in a cell-type specific fashion and appears to play an analogous function in self-avoidance in mouse amacrine cells. As the dosage of human Dscam has been implicated in Down Syndrome the studies described here may provide insight into the etiology of mental retardation associated with this syndrome.

项目概要/摘要果蝇 Dscam 基因编码一个庞大的免疫球蛋白 (Ig) 超家族蛋白家族，并发挥着重要作用。在调节发育过程中精确组织的神经回路的形成中发挥着至关重要的作用。选择剪接产生超过 38,016 种不同的亚型，其中包括 19,008 个与膜由两个可供选择的跨膜片段之一形成。这些胞外域共享相同的域结构，但三个可变域 Ig2、Ig3 和 Ig7 内的氨基酸序列不同。同工型共享相同的可变域组合（即它们在每个可变域处匹配）彼此结合，但是它们不与其他亚型结合。遗传分析表明 Dscam 在这种现象称为自我回避。每个神经元都表达一种独特的亚型组合，这使得它的神经突可以区分自我和非自我。自我识别，即异构体特异性同源性同一细胞的神经突之间的结合促进了这些过程之间的排斥。自我回避游戏在轴突分支的分离和树突域的形成中发挥重要作用，从而，有助于神经回路的组装。在这个提案中，我们将解决三个问题： 1. 是否是同质的识别对于 Dscam 的所有功能至关重要？为了解决这个问题，我们将生成以下基因的敲入突变体 Dscam 失去了参与同质结合的能力； 2. Dscam 是特定亚型吗在不同的神经元群体中表达？虽然 Dscam 显然在自我回避方面发挥了作用，但它仍然存在不同的神经元群可能使用 Dscam 的特定亚型来识别其他神经元。这一目标旨在识别此类细胞； 3. 它们对特定神经元的要求是不同的替代 Ig 域？为了解决这个问题，我们将用一个单行生成单独的苍蝇行 Ig2 结构域、单个 Ig3 结构域或单个 Ig7 结构域。虽然在哺乳动物中没有观察到 Dscam 多样性， Dscam 以细胞类型特定的方式表达，似乎在自我回避中发挥类似的功能在小鼠无长突细胞中。由于人类 Dscam 的剂量与唐氏综合症有关，因此研究这里描述的可能有助于深入了解与该综合征相关的精神发育迟滞的病因。