Centriole assembly and function for centrosome and cilia biology - PROJECT SUMMARY/ABSTRACT Overview. Centrioles and their associated centrosomes are crucial cellular organizers that maintain tissue health and support development. They control the cell's microtubule (MT) network, which provides the framework for multiple cellular functions: intracellular trafficking, signaling, genome segregation, cell morphology, and cell mobility. Throughout the cell cycle, centrioles change through new assembly and modifications to their scaffolding functions. In G0/G1, centrioles nucleate a primary cilium for cell sensation and signaling. During S- phase, they duplicate once and only once alongside the genome, and in mitosis, they organize the mitotic spindle. These mechanisms become disrupted in both cancer and trisomy 21 (T21, which causes Down syndrome). Further, in specialized multiciliated cells, centrioles are amplified and have an additional role in nucleating motile cilia that generate fluid flows essential for reproduction, development, and respiratory function. Despite their importance, many aspects of centriole control, function, and mechanical force resistance remain poorly understood. Goals for five years. Our research program comprises three main projects investigating centriole assembly, function, and regulation. RNA processing and RNA-binding proteins have emerged as critically important components of the centriole regulatory machinery. Project 1 will investigate the relationship between centrosome-associated RNAs, RNA- binding proteins, centrosome translational regulation, cell cycle control, and centriole duplication. We will study two RNA-binding proteins: UNK, which controls local translation during PLK4-induced centriole duplication and Big1, which modulates the Tetrahymena cell cycle and centriole number control. Project 2 will examine how trisomy 21 in Down syndrome affects cilia formation, specifically focusing on T21 repression of CP110 uncapping and the relationship between cilia-dependent Sonic Hedgehog and PKA signaling. Project 3 explores centrioles as force capacitors for motile cilia, examining both their resistance to mechanical forces and their role in promoting efficient ciliary movement and hydrodynamic flow. How triplet MT inner junction proteins and MT post- translational modifications strengthen centrioles and modify the ciliary wave form will be investigated. Vision for the program. Our research into centriole and centrosome biology, particularly regarding MT-dependent trafficking and mechanical force resistance, will advance our understanding of mechanobiology, development, and disease. RNA metabolism plays a vital role in development, and identifying mRNA processing events affecting centrioles and the MT network will help us understand how different cell types utilize their MT networks. Additionally, our T21 studies reveal promising directions for understanding cellular mechanisms in cardiac, immune, and secretory cell systems affected by Down syndrome.
