Identification of homologues of the Commissureless protein

描述(申请人提供)：神经系统左右两侧之间的神经连接对于协调和独立的运动至关重要。脊髓中这些连接的中断会导致脊柱弯曲(脊柱侧弯)，这种情况会限制体力活动，导致疼痛，并导致呼吸困难。在胚胎发育期间，中枢神经系统(CNS)中的许多生长神经会决定是否交叉到另一边。它们通过感知环境中的导航信号，利用细胞表面被称为受体的特殊蛋白质来做到这一点。控制哪些受体进入细胞表面，使神经元能够控制它们是否能对环境中的不同提示做出反应。对这一过程是如何控制的，人们知之甚少。在果蝇中，“不连结”或通信突变体的左右两侧之间根本没有神经联系。Comm蛋白控制着一类被称为ROBs的受体是否能够到达细胞表面。在人类中，Robo受体的遗传变异与脊柱侧弯和发育性阅读障碍等多种疾病有关。到目前为止，在昆虫之外还没有发现comm基因。这项提议旨在通过在果蝇身上使用定义明确的分析来测试来自其他物种的候选基因。鉴定其他物种的comm基因将为研究受体定位的控制开辟新的途径，并增加我们对神经如何在胚胎中准确地进行长距离导航的理解。它还可能有助于识别脊柱侧弯和其他神经连接模式改变的疾病的新基因。 与公共健康相关：这种不连结的基因在果蝇中枢神经系统中线的神经导航中发挥着核心作用，但脊椎动物的同源物尚未被确定。这项建议旨在确定功能同源物，增加我们对脊髓发育的了解。

DESCRIPTION (provided by applicant): Nerve connections between the left and right hand sides of the nervous system are critically important for coordinated and independent movements. Disruption of these connections in the spinal cord can lead to curvature of the spine (scoliosis), a condition that can restrict physical activity, cause pain and lead to problems breathing. Many growing nerves in the central nervous system (CNS) make a decision whether or not to cross to the other side during embryonic development. They do this by sensing navigational cues in their environment, using specialized proteins on their cell surface known as receptors. Controlling which receptors make it to the cell surface allows neurons to control whether or not they can respond to different cues in their environment. Understanding how this process is controlled is poorly understood. In the fruit fly, "commissureless" or comm mutants have no nerve connections between their left and right sides at all. The Comm protein controls whether or not a class of receptors called Robos can make it to the cell surface. In humans, genetic variants of Robo receptors have been implicated in such diverse conditions as scoliosis and developmental dyslexia. To date, comm genes have not been found outside of insects. This proposal aims to test candidate genes from other species by using well-defined assays in fruit flies. Identification of comm genes from other species will open new avenues to studying control of receptor localization, and add to our understanding of how nerves accurately navigate long distances in the embryo. It may also help identify a novel locus for scoliosis and other disorders in which nerve wiring patterns are altered. PUBLIC HEALTH RELEVANCE: The commissureless gene plays a central role in nerve navigation at the CNS midline of fruit flies, yet vertebrate homologues have not been identified. This proposal aims to identify functional homologues, increasing our understanding of spinal cord development.