Dynamics of Primary Cilia Formation During Mammalian Development

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Project Summary/Abstract Primary cilia are microtubule-based organelles that extend from the surface of mammalian cells and are specialized to respond to Hedgehog ligands and other signals. Abnormalities in primary cilia cause obesity, cystic kidney disease, and birth defects that affect development of the brain, skeleton and heart. Although primary cilia are widely distributed in embryonic and adult tissues, recent studies showed that the formation of primary cilia is regulated by lineage- and stage- dependent processes. The mechanisms that control cell-type specific primary cilia are not known. The goal of this project is to define the mechanisms that regulate primary cilia formation in specific tissues of the mouse embryo, with the long-term goal of developing therapies to restore or ablate cilia to treat human disease. Studies carried out in cells derived from mouse embryos will define the roles of specific proteins in the regulatory network that controls cilia initiation. The functions of specific proteins in that network, including RSG1, other RGK proteins and KIF24, will be validated in mutant mouse embryos. Studies will be carried out to determine why four specific cell types in the mouse embryo lack primary cilia: the extraembryonic endoderm (which contributes to the yolk sac of the fetus), the trophectoderm (an essential component of the placenta), the mature intestinal epithelium, and primordial germ cells. Developmental signals that regulate the dynamic gain or loss of primary cilia in the intestine and primordial germ cells will be identified. As it is clear that many regulators of tissue-specific formation of primary cilia have yet to be identified, screens will be carried out to identify genes that can promote formation of primary cilia in mouse extraembryonic endoderm stem cells, which never bear primary cilia.