Centrioles, which function as the essential template for ciliogenesis, are carefully maintained through different levels of regulation in vertebrate cycling cells. For example, we found that centrioles are converted to centrosomes (or the microtubule organization center) through stepwise modifications in a process called centriole-to-centrosome conversion (CCC). CCC enables the modified centriole, or the centrosome, to duplicate in S phase and to segregate equally in mitosis via the spindle, ensuring centriole/centrosome homeostasis. In addition, the presence and quality of the centrosome is further monitored by a separate surveillance program working with p53-mediated stress signaling to remove cells that have no or defective centrosomes. Finally, during vertebrate ciliogenesis, the centrosome can function more than just a template ? centrosomes are positioned deeply inside the cells where they organize microtubules and Golgi-mediated trafficking to regulate the spatial configuration of primary cilia, producing a mysterious type of cilia called submerged cilia. Instead of being at the cell surface as seen for typical cilia, submerged cilia are deliberately hidden by cells in a deep membrane invagination for reasons completely unknown. In this proposal, we seek to understand the molecular control of CCC, centrosome surveillance, and submerged cilia biogenesis.
s Centrosome and cilia dysfunction is prevalent in a wide range of diseases collectively called ciliopathy, including e.g. Bardet-Biedl syndrome, Joubert syndrome, Meckel-Gruber syndrome, polycystic kidney disease, and primary ciliary dyskinesia. However, the physiological role that these organelles play in most tissues remains elusive. A thorough understanding of the molecular pathways vertebrate cells employ to form and maintain the centrosome-cilium complex will allow for the development of therapeutic manipulations for some of these diseases.
Showing the most recent 10 out of 18 publications
