Control of centrosome biogenesis

Division Of Basic Sciences - Nci

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Abstract

The long-term goal of our laboratory is to understand the fundamentals of centrosome biology. Centrosomes are minute multifunctional membrane-less organelles present in only two copies in a typical cycling animal cell. In the core of a centrosome is a nine-fold symmetrical cylindrical microtubule-based structure called a centriole, which organizes the second major part of the centrosome called pericentriolar material which is a large and dynamic multiprotein complex and the site of many centrosomal functions. A typical somatic cell has only two centrosomes, often localized in the physical center of the cell near the nucleus. Centrosomes perform vital cellular functions such as microtubule nucleation, organization of the bipolar miotic spindle poles during cell division, cellular signaling, and they influence tissue architecture and cell motility. Centrosomes also organize sensory and motile cilia, which are critically important for development and tissue homeostasis. Centrosomes in disease: Supernumerary and/or structurally aberrant centrioles and centrosomes can initiate tumorigenesis, promote tumor invasiveness, and are present in almost all types of tumors. Centriolar or ciliary defects are, in addition, an underlying cause of genetic disorders known as ciliopathies. Therefore, understanding the molecular mechanisms that regulate centrosome number, structure, and function is a paramount for understanding centrosome and cilia- related diseases. Our research: Unlike most cellular organelles, which are present in variable shapes and numbers, centrosome architecture and number are stringently controlled. However, how cells control centrosome assembly has yet to be elucidated at a mechanistic level. We seek to develop an in-depth understanding of the mechanisms that regulate centriole and centrosome number and ensure centriole and centrosome numerical and structural stability (and how is this stability lost in pathologies like cancer). We aim to understand the roles of various cell cycle- and mitotic- regulators in centrosome biogenesis and how they coordinate centrosome assembly and with other cell cycle events. Finally, we are unraveling centrosomal architectural details in nano-scale resolution, to understand how intra-centrosomal dynamics of centrosomal proteins relates to centrosome functions. Methodology: We use a multipronged experimental approach combining molecular biology, biochemistry, and genetics, with a variety of cutting-edge microscopy approaches ranging from live-cell and super resolution microscopy, expansion microscopy, to transmission electron microscopy and correlative light and electron microscopy.