Regeneration and regrowth of sensory cilia via non-canonical mechanisms

描述（由申请人提供）：初级纤毛是基于微管的感觉细胞器，现在已知存在于人类和其他后生动物的几乎所有细胞类型中。纤毛包含信号分子，需要准确地感知和传导环境刺激。纤毛对外周化学、机械和光感神经元的感觉功能尤为重要。例如，嗅觉信号蛋白集中在嗅觉感觉神经元树突突起产生的纤毛上。嗅觉纤毛的破坏导致嗅觉缺失。同样，内耳纤毛的缺失会导致立体纤毛束的组织缺陷，从而导致听力异常。纤毛功能障碍是一系列疾病的基础，统称为纤毛病。纤毛的形成机制在物种间是高度保守的，从秀丽隐杆线虫和衣藻等模式生物中获得的见解有助于确定纤毛结构和功能所需的分子和机制。秀丽隐杆线虫感觉神经元的一个子集是纤毛的，和它们的脊椎动物一样，这些纤毛含有信号分子，对感觉传导至关重要。所有纤毛都是由高度保守的鞭毛内运输或IFT过程形成的；IFT基因功能缺失会导致严重的纤毛结构缺陷。我们做了一个令人惊讶的观察，纤毛样过程再生和再生在衰老的秀丽隐杆线虫的化学感觉神经元的一个子集缺乏IFT基因功能。这些过程类似于真正的纤毛，因为它们含有纤毛蛋白，并部分恢复感觉神经元的化学感觉功能。我们假设衰老通过秀丽隐杆线虫部分非规范的纤毛生成机制诱导纤毛再生或再生。这个探索性R21提案的总体目标是进一步研究之前描述的再生过程的机制。具体目的是：1)描述IFT突变体再生纤毛样结构的结构和功能。在这个目的中提出的实验将调查老年IFT突变体中再生的纤毛样结构的结构和功能在多大程度上类似于年龄匹配的野生型动物中的纤毛。2)研究老年IFT突变体纤毛样结构再生所需的机制。本实验将探讨衰老动物纤毛样结构再生的触发机制，并确定介导纤毛样结构再生的分子和途径。这项工作的结果将为未来实验的设计提供框架，旨在进一步表征这种先前描述的在缺乏核心IFT基因功能的情况下，年龄调节的纤毛再生现象。由于纤毛发生机制在整个门中都非常保守，我们期望我们的研究结果将对我们对纤毛产生和维持的认识产生重大影响，并可能为针对纤毛病和感觉神经元功能障碍提出新的途径和策略。

DESCRIPTION (provided by applicant): Primary cilia are microtubule-based sensory organelles that are now known to be present on nearly all cell types in humans and other metazoans. Cilia house signaling molecules and are required to accurately sense and transduce environmental stimuli. Cilia are particularly critical for the sensory functions of peripheral chem-, mechano- and photo-sensory neurons. For instance, olfactory signaling proteins are concentrated in the cilia that emanate from the dendritic knob of olfactory sensory neurons. Disruption of olfactory cilia results in anosmia. Similarly, loss of kinocilia in the inner ear reslts in defects in the organization of the stereocilia bundle leading to hearing anomalies. Ciliary dysfunction underlies a range of disorders and diseases collectively referred to as ciliopathies. Ciliogenic mechanisms are highly conserved across species, and insights from model organisms such as C. elegans and Chlamydomonas have been instrumental in defining molecules and mechanisms required for cilia structure and function. A subset of sensory neurons in C. elegans is ciliated and as in their vertebrate counterparts, these cilia contain signaling molecules and are essential for sensory transduction. All cilia are formed by the highly conserved process of intraflagellar transport or IFT; loss of IFT gene function results in severe ciliary structural defects. We made the surprising observation that cilia-like processes regenerate and regrow upon aging in a subset of chemosensory neurons in C. elegans lacking IFT gene function. These processes resemble bona fide cilia since they house ciliary proteins and partly restore chemosensory functions to the sensory neurons. We hypothesize that aging induces ciliary regrowth or regeneration via partly non- canonical ciliogenic mechanisms in C. elegans. The overall goal of this exploratory R21 proposal is to further investigate the mechanisms of this previously undescribed regeneration process. The Specific Aims are to: 1) Describe the structure and function of regenerated cilia-like structures in IFT mutants. Experiments proposed in this aim will investigate the extent to which the structure and function of the regenerated cilia-like structures in aged IFT mutants resemble those of cilia present in age-matched wild-type animals. 2) Investigate the mechanisms required for regrowth of cilia-like structures in aged IFT mutants. Experiments proposed in this aim will investigate the mechanisms by which regrowth of the cilia-like structures is triggered in aging animals, as well as identify the molecules and pathways which mediate the regrowth. Results from this work will provide the framework for the design of future experiments aimed at further characterizing this previously undescribed phenomenon of age-regulated ciliary regrowth in the absence of core IFT gene function. Since ciliogenic mechanisms are remarkably conserved across phyla, we expect that our findings will have major implications on our knowledge of cilia generation and maintenance, and may suggest new avenues and strategies to target ciliopathies and sensory neuron dysfunction.