Tissue-specific regulation of ciliary function by the transition zone

描述(申请人提供)：人体内的许多细胞从其表面有一个单一的突起，称为初级纤毛。虽然初级纤毛的存在早在一个多世纪前就被认识到了，但直到最近才清楚地知道，它们在检测和解释重要的细胞间线索方面发挥着作用。其中一些信号，如刺猬信号，是胚胎模式和成人组织动态平衡的关键调节因素。因此，Hedgehog信号的缺陷可能导致出生缺陷和某些形式的癌症。同样，初级纤毛缺陷可导致罕见的先天性综合征，如Meckel和Joubert综合征，可能是更常见的人类疾病，如多囊肾病的基础，并对一些癌症的进展很重要。有纤毛缺陷的哺乳动物细胞对刺猬信号没有反应。我们发现，在发育的特定时期，一些组织会被纤毛，而在成体组织中，一些细胞可以纤毛，而另一些细胞不会。我们假设，对哪些细胞纤毛的控制塑造了组织对纤毛解释的信号的反应。我们最近发现了一类新的基因，称为构造学，它在一些组织中支持纤毛发生，在另一些组织中控制纤毛膜的组成。构造学与纤毛疾病蛋白相互作用并共同定位于纤毛的一个亚域，称为过渡区。我们建议研究构造学及其相互作用，以了解睫毛功能的组织特异性调节。具体来说，我们将回答三个互补的问题：1)不同的构造是否调节不同组织中的纤毛发生？2)构造和其他过渡区成分是否通过调节蛋白质到纤毛的运输来促进纤毛发生？3)构造是否与人类疾病基因(如Meckel综合征和多囊肾病)一起调节纤毛发生？拟议的实验结合了遗传学、成像和生化方法，为这些问题提供了答案。这项工作将阐明构造学和相关蛋白质促进纤毛功能的机制，为纤毛如何在发育中发挥作用以及它们在人类纤毛疾病中如何失灵提供分子和细胞生物学见解。

DESCRIPTION (provided by applicant): Many cells in the human body possess a singular projection from their surface called a primary cilium. Although the existence of primary cilia has been recognized for over a century, only recently has it become clear that they function in the detection and interpretation of important intercellular cues. Some of these cues, such as Hedgehog signals, are key regulators of embryonic patterning and adult tissue homeostasis. Consequently, defects in Hedgehog signaling can cause birth defects and some forms of cancer. Similarly, defects in primary cilia can cause rare congenital syndromes such as Meckel and Joubert syndromes, may underlie more common human diseases such as polycystic kidney disease, and are important for the progression of some cancers. Mammalian cells with ciliary defects fail to respond to Hedgehog signals. We have found that some tissues are ciliated at specific times in development, and within adult tissues, some cells can be ciliated and others not. We hypothesize that the control of which cells are ciliated shapes how tissues respond to cilium-interpreted signals. We have recently identified a class of novel genes called the Tectonics, which support ciliogenesis in some tissues and control ciliary membrane composition in others. The Tectonics interact and co-localize with ciliary disease proteins at a subdomain of the cilium called the transition zone. We propose to study Tectonics and their interactors to understand the tissue-specific regulation of ciliary functions. Specifically, we will answer three complementary questions: 1) Do different Tectonics regulate ciliogenesis in different tissues? 2) Do Tectonics and other transition zone components promote ciliogenesis by regulating protein transport to the cilium? 3) Do Tectonics function with human disease genes, such as those underlying Meckel syndrome and polycystic kidney disease, to regulate ciliogenesis? The proposed experiments combine genetic, imaging and biochemical approaches to provide answers to these questions. This work will elucidate the mechanism by which Tectonics and associated proteins contribute to ciliary function, providing molecular and cell biological insights into how cilia function in development and how they misfunction in human ciliopathies.