How Cilia Are Built, Beat and Signal
To the Reiter Lab @ UCSF

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The development of a complex organism from a fertilized egg, one of biology's most astonishing transformations, relies on intercellular communication. Developmental genetics has successfully identified many of the signals that nature deploys to coordinate this development, and abnormalities in these signaling pathways underlie many diseases. Our lab uses the fruits of a large-scale mouse gene trap screen, as well as more classical mouse and zebrafish genetic tools, to identify novel intercellular signals.

Our genetic studies have led us to a specific interest in the primary cilium, a somewhat mysterious organelle. Most famously, primary cilia create the flow in the mouse node important for left-right axis formation. However, primary cilia exist on many other cells where their functions are unknown. We have uncovered a novel class of secreted factors conserved throughout metazoan evolution that are important regulators of ciliogenesis. Mutation of the founding member of this family results in a wide variety of developmental defects. Currently, we are using this mutant to elucidate the developmental functions of cilia.

Recently, others have shown that ciliary defects abrogate signaling by Hedgehog proteins. Defects in Hedgehog signaling are important causes of congenital birth defects and cancers. We have discovered that Smoothened, an essential component of the Hedgehog signaling pathway, moves to the primary cilium in response to Hedgehog stimulation. As disrupting this translocation prevents Hh signal transduction, we believe that the primary cilium is the site at which vertebrate Smoothened functions. We hypothesize that the cell's primary cilium acts as an antenna through which a variety of signals are sensed and transduced. Presently, we are investigating how those signals participate in development and disease.:

Our last aim is to use our knowledge of these signals to direct the differentiation of embryonic stem cells along defined lineages. Of particular interest is directing stem cells to become endodermal cells such as pancreatic cell types. The ultimate goal of the Reiter lab is to illuminate the function of novel signals in vertebrate development and to use our understanding of these signals to direct stem cells to become therapeutically useful cell types.