Our work seeks to understand the controls that regulate assembly and organization of the mitotic spindle and cilia assembly. Both of these processes are governed by the centrosome, an organelle that remains largely enigmatic. We are particularly interested in elucidating the molecular mechanisms that govern the switch between centriolar and basal body function, as the assembly of cilia from basal bodies is vital for a large number of developmental decisions. Many human birth defects, developmental abnormalities, and ciliopathies result from defective ciliogenesis or mutations in ciliary proteins. Recently, we have identified and characterized a centrosomal protein, CP110, and a cadre of associated proteins that play important roles in centrosome duplication, assembly of the mitotic spindle, and ciliogenesis. Ultimately, we hope to understand how this network of proteins regulates primary cilia assembly and function and how this process is disturbed in human developmental diseases. Recently, we identified several novel proteins that interact with CP110 and Cep97, including Talpid3 and WDR35, and we have begun to characterize the role of each protein in the context of cilia assembly. Mutations in Talpid3 and WDR35 give rise to developmental defects in diverse animal models, and mutations in WDR35 give rise to birth defects in humans. However, the mechanisms underlying the function of these proteins are not known. Our studies indicate that both proteins are involved in cilia assembly and function. Our proposal is based on three aims that use a combination of biochemistry, proteomics, cell biology, and RNAi. First, we will investigate the function of Talpid3 and WDR35 and ask how these proteins interact with the CP110 complex and how they direct cilia assembly. Next, we will ask how defects in these proteins lead to ciliary defects. We will investigate whether Talpid3 and WDR35 play roles in protein transport between vesicles and basal bodies/cilia and whether they regulate cell growth and quiescence. Third, we will perform biochemical screens to identify proteins that interact with Talpid3 and WDR35. In addition to explaining basic biochemical details regarding the role of CP110-associated proteins, trafficking of proteins into and out of the cilium, and ciliogenesis-processes that remain poorly understood--we will begin to understand the mechanisms underlying human ciliopathies and birth defects resulting from mutations in ciliary disease genes and the phenotypes associated with these diseases.
Cilia are sensory antenna-like organelles that emanate from the cell surface of nearly all quiescent and differentiated mammalian cells. Primary cilia play a critical role in mammalian development and defects in this organelle are thought to underlie a spectrum of human developmental diseases, birth defects, and cancer. This proposal seeks to understand the mechanisms that regulate ciliogenesis by focusing on novel protein interactions identified in our laboratory.
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|Fu, Wenxiang; Wang, Lei; Kim, Sehyun et al. (2016) Role for the IFT-A Complex in Selective Transport to the Primary Cilium. Cell Rep 17:1505-1517|
|Wang, Lei; Lee, Kwanwoo; Malonis, Ryan et al. (2016) Tethering of an E3 ligase by PCM1 regulates the abundance of centrosomal KIAA0586/Talpid3 and promotes ciliogenesis. Elife 5:|
|Sánchez, Irma; Dynlacht, Brian David (2016) Cilium assembly and disassembly. Nat Cell Biol 18:711-7|
|Miyamoto, Tatsuo; Hosoba, Kosuke; Ochiai, Hiroshi et al. (2015) The Microtubule-Depolymerizing Activity of a Mitotic Kinesin Protein KIF2A Drives Primary Cilia Disassembly Coupled with Cell Proliferation. Cell Rep :|
|Roosing, Susanne; Hofree, Matan; Kim, Sehyun et al. (2015) Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome. Elife 4:e06602|
|Kim, Sehyun; Lee, Kwanwoo; Choi, Jung-Hwan et al. (2015) Nek2 activation of Kif24 ensures cilium disassembly during the cell cycle. Nat Commun 6:8087|
|Fu, Wenxiang; Asp, Patrik; Canter, Brian et al. (2014) Primary cilia control hedgehog signaling during muscle differentiation and are deregulated in rhabdomyosarcoma. Proc Natl Acad Sci U S A 111:9151-6|
|Sánchez, Irma; Dynlacht, Brian D (2014) Cell biology: Short RNAs and shortness of breath. Nature 510:40-2|
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