Genetic Analysis of Kallmann Syndrome in C. elegans

描述（由申请人提供）：概述神经系统这种复杂结构的形成需要许多分子的协同作用，其中许多分子存在于分子复杂的细胞外基质（ECM）中。神经元接收并整合它们在ECM中遇到的具有专门受体的指导信号，并将其转化为定向生长反应。尽管许多引导分子的身份已经确定，但关于它们与ECM的相互作用以及这些相互作用如何控制它们的活性知之甚少。我们正在研究ECM的分子复杂性以及响应这种复杂性的信号分子如何定义神经元发育。KAL 1是一种细胞外神经粘附分子，在卡尔曼综合征中是突变的，卡尔曼综合征是一种具有特定神经元迁移和靶向缺陷的遗传性疾病。然而，KAL 1和潜在的相互作用伙伴在神经元发育中的分子功能仍然未知。我们在C中使用遗传方法。elegans中研究kal-1的功能（C. elegans直系同源物KAL 1）在神经系统发育中的作用。在遗传筛选中，我们已经确定了几个位点，与kal-1相互作用，其中三个意味着硫酸乙酰肝素，ECM的整体多糖成分的修改，在kal-1功能。本研究将分析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，并鉴定与kal-1相互作用并介导其功能的新基因。对KAL-1的研究将对神经元发育和疾病过程中ECM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座都是卡尔曼综合征分子上难以捉摸的候选基因。项目叙述：KAL-1是细胞外间隙的细胞粘附分子，其在卡尔曼综合征中是突变的，卡尔曼综合征是具有神经元靶向和迁移缺陷的遗传性疾病。我们在C中使用遗传方法。elegans，以了解其他基因kal-1在神经元发育和疾病中的功能。

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.