Cell Recognition in the developing Drosophila Brain

项目摘要/摘要 果蝇Dscam基因编码免疫球蛋白(Ig)超家族蛋白的一个庞大家族，并在 在发育过程中对精确组织的神经回路的形成起着至关重要的调节作用。备择 剪接产生超过38,016种不同的异构体，包括19,008个与 通过两个可供选择的跨膜片段中的一个跨膜。这些外域共享相同的域 结构，但在三个可变区，IG2，IG3和Ig7的氨基酸序列不同。异构体共享 可变区的相同组合(即，它们在每个可变区匹配)彼此结合，但是 它们不与其他异构体结合。遗传分析表明，Dscam在一种 这一现象被称为自我回避。每个神经元都表达独特的异构体组合，这使得 它的神经突起来区分自我和非我。自我识别，即同型异型的同型异性者 同一细胞的神经突起之间的结合促进了这些突起之间的排斥。自我回避游戏 在轴突分支的分离和树突域的形成中起着重要作用，因此， 有助于神经回路的组装。在这项提案中，我们将解决三个问题：1.同性恋 认知度对DSCAM的所有功能至关重要？为了解决这个问题，我们将产生敲入突变体 Dscam已经失去了参与亲性结合的能力；2.Dscam是Dscam的特定亚型吗 在不同的神经元群体中表达？虽然Dscam显然在自我回避中发挥了作用，但它仍然 不同的神经元群体可能使用特定的Dscam亚型来识别其他神经元。 这个目的是为了识别这样的细胞；以及3.它们在特定神经元中是否需要 不同的替代Ig域？为了解决这个问题，我们将用一个单独的 IG2结构域、单个IG3结构域或单个Ig7结构域。虽然在哺乳动物身上没有观察到Dscam的多样性， DSCAM以细胞类型特有的方式表达，似乎在自我回避中扮演着类似的功能 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，研究 这里所描述的可能对与这种综合征相关的精神发育迟缓的病因提供了洞察力。

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.