Nephronophthisis-related ciliopathies and ciliary specialization

项目摘要 纤毛在人类发育和健康中起着至关重要的作用。纤毛的普遍性和多样性得到了反映 在由纤毛缺陷引起的多症状纤毛病变中。纤毛病基因突变的临床严重程度各不相同 细胞类型之间的关系，包括囊性肾病，神经和骨骼缺陷，视网膜变性， 反位和男性不育症。而相同的基本鞭毛内转运(IFT)机制构建了所有 纤毛和鞭毛，纤毛专化的机制还知之甚少。例如，纤毛 产生细胞外小泡(EV)。EV脱毛是纤毛的一般属性还是特殊的 某些纤毛类型的特征尚不清楚。纤毛EVS的功能及其在纤毛疾病中的作用 也鲜为人知。该项目的长期目标是确定调节纤毛的分子机制。 特化、重塑、可塑性、EV生物发生和EV功能。线虫内唇型纤毛 2(IL2)神经元表现出几种特化：它们有独特的微管超微结构，特化的IFT， 然后甩掉电动汽车。IL2纤毛移行区(TZ)和轴丝在结构上是可塑性的，并从一个 动物发育过程中的结构：从典型的9+0结构到非典型的6+0结构。而当 纤毛和鞭毛具有9倍的微管双重对称性，观察到微管数量的变化。 在自然界中。肾初级纤毛不符合9+0范式。这种发育可塑性表明 有些纤毛缺陷(睫毛病变)可能会在以后得到矫正。我们的假设得到了最近的 发现常染色体显性遗传性多囊肾病是可逆的，肾脏表现为 结构可塑性。我们的简单线虫模型使我们能够揭示调节纤毛的机制 重塑和可塑性。我们发现TZ重塑需要IFT和微管蛋白密码子的联合使用 微管蛋白亚型、谷氨酰化和微管相关蛋白。肾单位相关的纤毛病变 (NPHP-RCS)与TZ相关蛋白的缺陷有关。NPHP-RCS包括肾单位肾炎、 Meckel Gruber(MKS)、Joubert(JBTS)和老年LøKen综合征。慢性阻塞性肺疾病患者功能丧失的临床严重性 Nphp-rc基因因细胞和纤毛类型不同而不同，因此了解纤毛和肠道病毒生物学是非常必要的。 在各种不同的背景下。我们将使用线虫来确定驱动移行区和轴丝的机制 非典型主纤毛的重塑和可塑性。睫状体EV的脱落是一种保守的现象，但人们对此知之甚少 关于cilia如何以及为什么制造电动汽车。我们将测试睫状体重塑和非正规性 结构影响EV的生物发生和EV功能。

Project Summary Cilia play essential roles in human development and health. Ciliary ubiquity and diversity are reflected in multi-symptom ciliopathies caused by ciliary defects. The clinical severity of ciliopathy gene mutations varies between cell types and includes cystic kidney disease, neurological and skeletal defects, retinal degeneration, situs inversus, and male infertility. While the same basic intraflagellar transport (IFT) machinery constructs all cilia and flagella, the mechanisms underlying ciliary specialization are poorly understood. For example, cilia produce extracellular vesicles (EVs). Whether EV shedding is a general property of cilia or a specialized feature of some cilia types is unknown. The functions of ciliary EVs and their contributions to ciliopathies are also poorly understood. The long-term goal of this project is to identify molecular mechanisms regulating ciliary specialization, remodeling, plasticity, EV biogenesis, and EV functions. Cilia of the C. elegans inner labial-type 2 (IL2) neurons display several specializations: they have unique microtubule ultrastructure, specialized IFT, and shed EVs. The IL2 ciliary transition zone (TZ) and axoneme is structurally plastic and remodels from one structure to another during animal development: from a canonical 9+0 to non-canonical 6+0 structure. While cilia and flagella share a 9-fold microtubule doublet symmetry, variations in microtubule numbers are observed in nature. Renal primary cilia do not conform to the 9 + 0 paradigm. This developmental plasticity suggests that some ciliary defects (ciliopathies) may be corrected at later times. Our hypothesis is supported by the recent discovery that autosomal dominant polycystic kidney disease is reversible, and that the kidney displays structural plasticity. Our simple C. elegans model allows us to uncover mechanisms that regulate ciliary remodeling and plasticity. We found that TZ remodeling requires IFT and the tubulin code – combinatorial use of tubulin isotypes, glutamylation, and microtubule-associated proteins. Nephronophthisis-related ciliopathies (NPHP-RCs) are associated with defects in TZ-associated proteins. NPHP-RCs include nephronophthisis, Meckel Gruber (MKS), Joubert (JBTS), and Senior-Løken syndromes. The clinical severity of loss of function of NPHP-RC genes varies between cell and cilia types, thus it is imperative to understand ciliary and EV biology in a variety of contexts. We will use C. elegans to identify mechanisms driving transition zone and axonemal remodeling and plasticity in non-canonical primary cilia. Ciliary EV shedding is a conserved, yet little is known about how and why cilia make EVs. We will test the hypotheses that ciliary remodeling and a non-canonical structure impacts EV biogenesis and EV function.