Genetic Analysis of Kallmann Syndrome in C. elegans

描述(申请人提供)：概述神经系统如此精细的结构的形成需要众多分子的协同作用，其中许多分子存在于分子复杂的细胞外基质(ECM)中。神经元接收和整合它们在ECM中遇到的指导信号和专门的受体，并将它们转化为定向生长反应。虽然许多引导分子的身份已经确定，但人们对它们与ECM的相互作用以及这些相互作用如何控制它们的活动知之甚少。我们正在研究ECM的分子复杂性以及对这种复杂性做出反应的信号分子如何定义神经元发育。KAL1是一种细胞外神经黏附分子，在Kallmann综合征中是突变的，Kallmann综合征是一种遗传性疾病，具有特定的神经元迁移和靶向缺陷。然而，KAL1和潜在的相互作用伙伴在神经元发育中的分子功能仍不清楚。我们正在使用线虫的遗传学方法来研究Kal-1(线虫KAL1的同源基因)在神经系统发育中的功能。在基因筛查中，我们已经确定了几个与Kal-1相互作用的基因座，其中三个基因座暗示了Kal-1功能中硫酸乙酰肝素的修饰，这是ECM的组成部分。这项研究将分析Kal-1在神经系统发育中的功能，确定Kal-1与硫酸乙酰肝素蛋白多糖的相互作用，并寻找与Kal-1相互作用的新基因，并在体内介导其功能。对KAL-1的研究将对神经元发育和疾病过程中细胞外基质和KAL-1功能之间的复杂关系提供重要的见解。重要的是，我们发现的任何新的基因位点都是Kallmann综合征分子难以捉摸的病例的候选基因。项目简介：KAL-1是一种细胞外间隙的细胞黏附分子，在Kallmann综合征中是突变的，Kallmann综合征是一种具有神经元靶向和迁移缺陷的遗传病。我们正在使用线虫的遗传学方法，以了解其他基因kal-1如何以及与哪些基因一起在神经元发育和疾病中发挥作用。

DESCRIPTION (provided by applicant): Summary Formation of such an elaborate structure as the nervous system requires the concerted action of numerous molecules many of which reside in the molecularly complex extracellular matrices (ECMs). Neurons receive and integrate the guidance signals they encounter in the ECMs with specialized receptors and translate them into a directed growth response. Whereas the identity of many guidance molecules has been determined, very little is known about their interactions with the ECM's and how these interactions control their activity. We are investigating how the molecular complexity of ECMs together with the signaling molecules that respond to this complexity define neuronal development. KAL1 is an extracellular neural adhesion molecule that is mutant in Kallmann Syndrome, a hereditary disorder with specific neuronal migration and targeting defects. However, the molecular function of KAL1 and potential interacting partners in neuronal development remains unknown. We are using a genetic approach in C. elegans to study the function of kal-1 (the C. elegans ortholog of KAL1) in nervous system development. In a genetic screen we have identified several loci that interact with kal-1 three of which imply modifications of heparan sulfate, integral polysaccharide components of the ECMs, in kal-1 function. This research will analyze the function of kal-1 in nervous system development, define the interactions of kal-1 with heparan sulfate proteoglycans and identify novel genes that interact with kal-1 and mediate its function in vivo. The study of KAL-1 will give important insights into the intricate relationship between ECM's and KAL-1 function during neuronal development and disease. Importantly, any novel locus that we identify is a candidate gene in molecularly elusive cases of Kallmann Syndrome. Project Narrative: KAL-1 is a cell adhesion molecule of the extracellular space which is mutant in Kallmann Syndrome, a genetic disease with neuronal targeting and migration defects. We are using a genetic approach in C. elegans in order to understand how and with which other genes kal-1 functions during neuronal development and disease.