Tissue-specific regulation of ciliary function by the transition zone

描述（由申请人提供）：人体内的许多细胞在其表面具有单一的突起，称为初级纤毛。虽然初级纤毛的存在已经被认识了一个多世纪，但直到最近才清楚它们在检测和解释重要的细胞间信号方面的作用。其中一些线索，如刺猬信号，是胚胎模式和成体组织稳态的关键调节因子。因此，Hedgehog信号的缺陷会导致出生缺陷和某些形式的癌症。同样，原发纤毛缺陷可引起罕见的先天性综合征，如Meckel综合征和Joubert综合征，可能是多囊肾病等更常见的人类疾病的基础，并且对某些癌症的进展很重要。具有纤毛缺陷的哺乳动物细胞不能响应刺猬信号。我们发现一些组织在发育的特定时期是有纤毛的，在成人组织中，一些细胞可以纤毛，而另一些细胞则不能。我们假设纤毛细胞的控制决定了组织对纤毛信号的反应。我们最近发现了一类被称为构造的新基因，它支持某些组织的纤毛发生，并控制其他组织的纤毛膜组成。该结构与纤毛疾病蛋白在纤毛的一个亚结构域称为过渡区相互作用和共定位。我们建议研究构造及其相互作用，以了解睫状体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)不同的构造是否在不同的组织中调节纤毛的发生？2)构造和其他过渡带成分是否通过调节蛋白质向纤毛的运输来促进纤毛的发生？3)构造是否与人类疾病基因（如Meckel综合征和多囊肾病的潜在基因）一起调节纤毛的发生？提出的实验结合了遗传、成像和生化方法来提供这些问题的答案。这项工作将阐明构造和相关蛋白对纤毛功能的作用机制，为纤毛在发育过程中的功能以及它们在人类纤毛病中的功能失调提供分子和细胞生物学的见解。

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.