Ciliopathies comprise disorders associated with aberrant function of essential organelles called cilia. Cilia are found in almost all vertebrate cells, with a subset of this population being motile and/or multiciliated. Over 1,000 proteins have been associated with the ciliary proteome, yet the regulatory circuit controlling the formation of cilia remains lesser known. Our lab has identified transcription factors and coactivators that contribute to the ciliogenesis circuit. Such factors include orphan nuclear receptor Esrrγ and coactivator Ppargc1a/PGC1a. Independently, these factors regulate both mono- and multi-ciliated cells in the early signaling node, ear, and embryonic kidney (pronephros). Absence of these factors results in decreased multiciliated cells, decreased cilia length, and increased unciliated basal bodies. Considering these phenotypic similarities, we hypothesized a cooperative relationship between Esrrγ and Pppargc1a in the context of ciliated cell development. By modelling dual heterozygosity with genetic interaction studies, we found that ppargc1a works synergistically with esrrγa to regulate prostaglandin signaling to support ciliary outgrowth and multiciliated cell fate choice. While previous studies have alluded to the interaction of Esrrγ and Ppargc1a/PGC1a in metabolism, this is the first report of a cooperative effect that is essential for ciliogenesis or lineage decisions in development. This study has far-reaching implications, as cilia are present in various tissues, and these factors may serve as therapeutic targets for ciliopathic conditions and birth defects.
Graduate Women in Science Fellowship, Warren Center for Drug Discover Welter Family Fellowship, Notre Dame Center for Stem Cells and Regenerative Medicine Fellowship, University of Notre Dame startup funds.
