Transition zone control of ciliary signaling
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Investigator: Jeremy Reiter, MD, PhD
Sponsor: NIH National Institute of General Medical Sciences
Location(s): United States
Description
Primary cilia are small projections found on many human cells involved in receiving and interpreting signals from other cells. Disruption of these ciliary signaling events contributes to birth defects, cancer, polycystic kidney disease, and other human disorders. We will investigate how cells control which signaling proteins are at cilia to provide a mechanistic understanding of the origins of cilia-related diseases.
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.