The role of primary cilia in craniofacial development

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DESCRIPTION (provided by applicant): Almost every cell in the body is equipped with a membrane bound, finger-like projection called a primary cilium. Cilia have been equated to cellular antennae that detect molecular signals in the environment and thus influence how cells behave as a consequence. Ciliary defects, referred to as ciliopathies, are associated with a broad of human diseases and disorders. A significant number of ciliopathies affect the craniofacial complex. The facial prominences and their associated skeletal elements are derived from cranial neural crest cells. Herein, I will investigate how cilia function during the ontogeny of cranial neural crest cells. After mapping the presence of primary cilia on neural crest cells during distinct phases of development, I will disrupt primary cilia in neural crest cells by inactivating one of the kinesin-ll motor subunits, Kif3a a protein essential for primary cilia function, an determine if neural crest cells are able to transition from an epithelial cell type to a mesenchymal cell, migrate, proliferate, and form mesenchymal condensations. Finally, I will determine if primary cilia direct neural crest migration by detecting a molecular signal and orienting the cells towards that signal. Taken together these experiments precisely dissect how the primary cilia direct the development of the cells that give rise the cranial skeleton. My immediate goal is to precisely define the role of primary cilia in neural crest development using an avian model system. I plan to use my remaining time as a post-doctoral fellow to further explore strategies to inactivate genes essential for primary cilia function. 1 will utilize the expertise of my advisory committee to introduce me to the alternative approaches to gene inactivation in that can be applied to both avian and zebrafish model systems. These early experiments will be performed in the rich academic environment of Stanford University. My long term goal is to establish an independent research program that uses multiple animal model systems (frog, fish, chick, and mouse) to study craniofacial patterning. 1 plan to build on my measurable experience in each model to exploit the benefits of each system to address particular questions concerning species-specific craniofacial development and patterning. Public Health Relevance: Primary cilia are ubiquitous organelles that play vital roles in signal transduction. Defects in primary cilia are responsible for a poorly defined class of defects called ciliopathies. A significant number of ciliopathies affect craniofacial development. The goal of this proposal is to explore the basis for ciliopathies with craniofacial phenotypes.