The primary cilium is critical to vertebrate development and the prevention of disease. Severe defects in this organelle lead to prenatal lethality in extreme cases and a variety of structural birth defects and degenerative diseases in less extreme cases. It is thought that the primary cilium serves as a cellular antenna to monitor the extracellular environment and feed information back to the cell to coordinate its action with that of the surrounding cells. A large number of signaling pathways are directly or indirectly regulated by cilia including hedgehog, left-right/nodal, Wnt, notch, IGF and PDGF. Understanding how the cilium is assembled and how the signaling environment is created and maintained is critical to understanding how this organelle functions in the etiology of human diseases. The cilium is assembled by the process of intraflagellar transport (IFT) where large protein complexes called IFT particles are carried along the ciliary microtubules by kinesin and dynein motors. The IFT system consists of about 20 proteins organized into two large complexes. The long-term objective of this work is to understand the function of the individual IFT particle proteins. Mutations in most Ift genes block ciliary assembly and also disrupt ciliary signaling. In the past, it has been difficult to separate the function of IFT in building a cilium, which is required for signaling, from functions directly in signaling. This proposal focuses on Ift25 and Ift27, which unlike most Ift genes in mouse are not required for ciliary assembly but like other Ift genes are required for hedgehog signaling. In that absence of IFT25 or IFT27, the hedgehog receptors patched-1 and smoothened are not trafficked properly and accumulate in cilia. This proposal addresses how IFT25 and IFT27 function to connect IFT to the dynamic movements of hedgehog components into and out of cilia. This will be addressed through a series of protein interaction studies, live cell imaging and mouse genetics.
Severe defects in the primary cilium cause prenatal lethality while less severe defects result in a variety of diseases including polycystic kidney disease and blindness along with a group of syndromes called the ciliopathies. These syndromes, which include Bardet-Biedl, Meckel Gruber and Jeune Syndromes, often present with cystic kidney disease and blindness along with a variety of symptoms including obesity, mental retardation, and structural birth defects. This proposal seeks to understand the mechanism by which cilia are assembled and function to ultimately drive the identification of a treatment or cure for these diseases.
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