Genetic analysis of signaling pathways in cilia assembly and remodeling

PROJECT SUMMARY Primary cilia mediate transduction of all major signaling pathways, which in turn modulate cilia morphology and functional outputs. The research in my lab is focused on identifying new genes and mapping signaling networks that regulate cilia assembly during development and cilia remodeling in response to

environmental stress at single-cell resolution in vivo. To pursue these research questions, we use sophisticated molecular genetics, proteomics, and live imaging approaches in C. elegans with complementary studies in mammalian cell culture models. In the next five years, we propose to address three research goals. A first

major goal is to define molecular mechanisms that regulate heterotrimeric G protein signaling during cilia morphogenesis. Heterotrimeric G proteins and their canonical activators G protein coupled receptors (GPCRs) localize to cilia, modulate cilia morphology, and when disrupted cause genetic disorders in humans. Key

outstanding questions that we propose to address are: What conserved and species-specific mechanisms regulate ciliary trafficking of heterotrimeric G proteins? How do non-canonical, GPCR-independent mechanisms modulate functions of ciliary G proteins? A second major goal is to determine in vivo mechanisms

that regulate and mediate cilia remodeling in response to stress. After exposure to environmental stress, primary cilia undergo structural remodeling, which is associated with altered signaling output. We want to know how stress modulates signaling capacity of cilia in vivo. What are the stress- and cell-specific mechanisms of

stress-induced cilia dynamics? A third major goal is to identify new conserved genes and pathways in cilia morphogenesis and function. Cell- and tissue-specific differences in the ciliogenic programs are not well understood, and the causative genes for many ciliopathy cases are unknown. For example, nearly 40 percent

of individuals with neurodevelopmental ciliopathies are estimated to be without genetic diagnosis. We want to harness the power of bioinformatic approaches and C. elegans genetics to ask – what are the developmental mechanisms that operate in cell-specific contexts to assemble cilia? Collectively, these projects will generate

fundamental insight into cell-specific signaling networks that regulate cilia assembly, remodeling, and cilia- mediated cellular functions. This knowledge is an important steppingstone toward better understanding of the genetic basis of ciliopathies, and more broadly, of mechanisms that allow cells to communicate with their

environment. This award would also allow us to recruit and train a diverse pool of researchers, launch new collaborations, and follow new hypotheses that emerge in the course of this study.