Transition zone control of ciliary signaling

 描述（由申请人提供）：人体中的许多细胞从其表面具有称为初级纤毛的单一突起。虽然初级纤毛的存在已被确认超过一个世纪，直到最近才变得清楚，他们的功能在检测和解释重要的细胞间的线索。其中一些线索，如刺猬信号，是胚胎模式和成人组织稳态的关键调节因子。因此，Hedgehog信号的缺陷可能导致出生缺陷和某些形式的癌症。类似地，原发性纤毛缺陷导致先天性综合征，如Meckel和Joubert综合征，可以成为更常见的人类疾病如多囊肾病的基础，并且对于某些癌症的进展至关重要。 为了在信号传导中发挥作用，初级纤毛需要保持与细胞周围部分不同的组成。我们确定过渡区（睫状体基底的一个区域）是睫状体组成的关键调节因子。为了了解过渡区如何控制哪些蛋白质定位于纤毛，我们将回答三个互补的问题。 首先，鉴于过渡区是纤毛的一个复杂且高度结构化的区域，我们将确定它是如何构建的。识别过渡区的结构以及它是如何被纤毛病变突变破坏的，将为纤毛信号传导缺陷的起源提供结构上的见解。 第二，我们将研究 过渡区调节蛋白质进入纤毛、离开纤毛，或作为纤毛基部的扩散屏障。了解不同的成分如何赋予过渡区不同的特征将有助于揭示这个门如何控制纤毛成分。第三，我们将研究不同的复合物如何在过渡区合作，以支持纤毛发生和纤毛信号。这些实验将有助于阐明不同过渡区成分的突变如何导致小鼠和人类不同的发育表型。 通过阐明过渡区控制纤毛组成的机制，我们将了解细胞如何将这种细胞器划分为在哺乳动物发育过程中执行关键的信号功能。

 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 cause congenital syndromes such as Meckel and Joubert syndromes, can underlie more common human diseases such as polycystic kidney disease, and are essential for the progression of some cancers. To function in signaling, primary cilia need to maintain a different composition than surrounding parts of the cell. We identified the transition zone, a region of the ciliary base, as a critical regulator of ciliary composition. To understand how the transition zone controls which proteins localize to cilia, we will answer three complementary questions. First, given that the transition zone is a complex and highly structured region of the cilium, we will determine how it is built. Identifying the architecture of the transition zone and how it is disrupted by ciliopathy mutations will provide structural insights into the origins of ciliary signaling defects. Second, we will examine whether the transition zone regulates protein entry into the cilium, exit from the cilium, or acts as a diffusion barrier at the ciliary base. Understanding how different components impart different characteristics to the transition zone will help reveal how this gate controls ciliary composition. Third, we will examine how different complexes cooperate within the transition zone to support ciliogenesis and ciliary signaling. These experiments will help elucidate how mutations in different transition zone components result in different developmental phenotypes, both in mice and humans. By elucidating the mechanisms by which the transition zone controls ciliary composition, we will understand how the cell compartmentalizes this organelle to perform critical signaling functions during mammalian development.