Mechanisms generating ciliary structural diversity in C. elegans

描述（由申请人提供）：初级纤毛现在被认为存在于所有哺乳动物细胞类型中，并作为环境传感器。一般来说，这些纤毛的结构相对简单。然而，感觉细胞类型，如耳中的肌纤毛和嗅觉感觉纤毛，表现出高度特化的纤毛结构，这对它们的特殊感觉功能至关重要。虽然现在对初级纤毛的形成已经了解很多，但对特殊纤毛的形成和维持过程了解甚少。纤毛或嗅觉纤毛功能的丧失会导致听力丧失和嗅觉丧失。因此，了解这些特殊纤毛的形成和功能对于全面了解动物的嗅觉和听觉是至关重要的。秀丽隐杆线虫是研究特化纤毛形成机制的良好模型系统。秀丽隐杆线虫的几种化学感觉神经元表现出高度特化的纤毛，这对它们的感觉功能至关重要。本研究的目的是确定产生特殊化学感觉纤毛类型所需的遗传机制。利用基于蛋白质组学的方法，一个非常规的肌球蛋白HUM-4被确定为候选纤毛分子。humm -4的突变导致纤毛缺陷，特别是在嗅觉神经元类型中。非常规肌球蛋白先前与内耳纤毛和立纤毛结构的维持有关，并在Usher综合征等听力障碍综合征中发生突变。本研究的目的是研究HUM-4在秀丽隐杆线虫模型系统中产生特殊嗅纤毛形态的功能。这些纤毛结构对于神经元特异性的化学感觉反应是必不可少的，所以感觉神经元是如何专门用于其独特功能的也将被描述。建议的具体目标是：1。HUM-4非常规肌球蛋白在纤毛形态调控中的作用。2. HUM-4非常规肌球蛋白调控AWB纤毛形态的机制探讨。

DESCRIPTION (provided by applicant): Primary cilia are now believed to be present in all mammalian cell types and act as environmental sensors. Generally, these cilia exhibit relatively simple structures. However, sensory cell types such as the kinocilia in the ear and olfactory sensory cilia exhibit highly specialized cilia structures that are essential for their specialized sensory functions. Although much is now known about how primary cilia are formed, very little is understood about the processes of building and maintaining specialized cilia. Loss of kinocilia or olfactory cilia function result in hearing loss and anosmia. Thus, understanding how these specialized cilia form and function is essential for a complete understanding of how animals smell and hear. C. elegans is an excellent model system in which to study the mechanisms of specialized cilia formation. Several chemosensory neuron types in C. elegans exhibit highly specialized cilia, which are essential for their sensory functions. The goal of this research is to define the genetic mechanisms required for the generation of specialized chemosensory cilia types. Using a proteomics-based approach, an unconventional myosin HUM-4 was identified as a candidate ciliary molecule. Mutations in hum-4 lead to ciliary defects specifically in an olfactory neuron type. Unconventional myosins have previously been implicated in maintenance of both kinocilia and stereocilia structures in the inner ear, and are mutated in hearing disorder syndromes such as Usher syndrome. The goal of this proposal is to investigate the functions of HUM-4 in the generation of specialized olfactory cilia morphology in the C. elegans model system. These cilia structures are essential for neuron-specific chemosensory responses so how sensory neurons are specialized for their unique functions will also be described. The proposed specific aims are: 1. Characterization of the role of the HUM-4 unconventional myosin in the regulation of ciliary morphology. 2. Elucidation of the mechanism by which the HUM-4 unconventional myosin regulates AWB ciliary morphology. PUBLIC HEALTH RELEVANCE: A thorough understanding of these mechanisms is important for a complete understanding of how humans hear and smell. This work will lead to a better understanding of how specialized cilia are formed, and how defects in cilia structure lead to sensory dysfunction.