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Our lab has two main interests: 1) Understanding the mechanisms involved in cell-cell signaling through the vertebrate Hedgehog pathway; and 2) Synthesizing and validating new chemical probes for microscopic imaging and functional assays of various biological molecules (nucleic acids, proteins, lipids), in cells and in animals.

1) Mechanisms of Hedgehog signaling
The Hedgehog pathway plays a critical role in developing embryos as well as in the maintenance of adult stem cells. Unregulated Hedgehog signaling is implicated in a large number of human cancers. We are using biochemistry, cell and chemical biology to elucidate how vertebrate cells send and respond to Hedgehog signals. The key questions of Hedgehog signaling that we are investigating are:

A) How is the secreted Hedgehog protein activated?
Hedgehog becomes active through a unique posttranslational process involving the attachment of both cholesterol and palmitate. We are using biochemistry and cell biology to dissect the mechanism of these reactions, as well as to understand how Hedgehog is secreted. Finally, we are using chemical biology approaches to identify other cholesterol-modified proteins and study them functionally in cells.

B) How does Hedgehog signaling control the Gli transcription factors?
In vertebrates, Hedgehog signaling initiated in primary cilia activates the membrane protein Smoothened and leads to activation of Gli proteins, the transcriptional effectors of the pathway. In the absence of signaling, Gli proteins are inhibited by the cytoplasmic protein SuFu. We found that Hedgehog stimulation quickly recruits endogenous SuFu-Gli complexes to cilia and causes rapid dissociation of the SuFu-Gli complex, thus allowing Gli to enter the nucleus and activate transcription. We are using biochemical reconstitution and cell biology to dissect this simple mechanism of vertebrate Hedgehog signaling. We plan to use live cell imaging to understand the spatial and temporal aspects of SuFu-Gli regulation by Hedgehog signaling at the primary cilium.

C) What is the role of primary cilia in Hedgehog signal transduction?
Primary cilia are microtubule-based processes that serve as "cellular antennas" that sense and transduce various external stimuli. Cilia are required for Hedgehog signaling in vertebrates, and ciliary defects cause diseases called ciliopathies, characterized by impaired Hedgehog signaling. In spite of their critical importance, how cilia organize Hedgehog signaling remains a mystery. We are using microscopy, chemical biology and biochemistry to understand the dynamics of Hedgehog signal transduction in primary cilia. We are particularly interested in deciphering the mechanism of the tumor suppressor Patched (the Hedgehog receptor), and elucidating how cholesterol derivatives regulate the membrane protein Smoothened in cilia. Finally, we are interested in discovering novel components of Hedgehog signaling in cilia, as well as small molecule inhibitors of the Hedgehog pathway that function by antagonizing sterols.

2) Novel chemical probes for imaging and studying biological molecules
Our lab is developing and using new chemical probes for metabolically labeling biological molecules, followed by their detection through bio-orthogonal chemical reactions. Past work focused on high-resolution microscopy probes for DNA, RNA and choline phospholipids. We are currently developing, characterizing and using probes for nascent proteins, sterols, and other classes of phospholipids.

Last Update: 6/24/2014

Publications

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© 2014 by the President and Fellows of Harvard College