Transition zone control of ciliary signaling

项目总结/文摘

Project summary/Abstract 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, it has become clear only recently 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 ciliopathies such as Oro-facio-digital and Joubert syndromes, and can underlie more common human diseases such as polycystic kidney disease. 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 how extra-ciliary protein complexes generate the transition zone will illuminate how mutations affecting non-ciliary proteins also cause ciliopathies. Second, we will examine how the transition zone regulates protein and lipid localization to the cilium. Understanding how different trafficking machines and their cargos use distinct mechanisms to cross the transition zone will help reveal how this gate controls ciliary protein composition. Additionally, we will build on recent data that the lipid composition of the ciliary membrane is specialized and essential for its signaling functions by examining how ciliary lipids enter the cilium and enriched there by the transition zone. These experiments will demonstrate how proteins regulate lipid composition to enable organelle-specific functions. Third, we will determine how the transition zone regulates craniofacial development. Many ciliopathies are associated with craniofacial defects, and our investigation of how transition zones function in facial patterning is revealing novel ways in which ciliary signaling regulates mammalian development. By elucidating the mechanisms by which the transition zone controls ciliary composition, we will help illuminate how the cell compartmentalizes this organelle to perform diverse signaling functions critical for development and physiological functioning.