Cells receive many cues from their environment that need to be processed properly in order to ascertain correct cellular function. In recent years, the primary cilium, a microtubule-based organelle, has been shown to function as a 'cellular antenna'. The cilium protrudes from the cell membrane and as such it is exposed to the extracellular environment and can receive signals. The importance of this unconventional organelle is clearly illustrated by a large group of human developmental disorders, the ciliopathies, that are caused by defects in ciliary structure and function. The Hedgehog signaling pathway - a developmental signaling cascade that establishes the embryonic body plan - relies on a properly constructed cilium for signal transduction. Many of the symptoms of ciliopathies can therefore be related back to impaired Hedgehog signal transduction. While the link between the primary cilium and Hedgehog signal transduction has been well-established, the underlying molecular mechanisms are much less well understood.
The goal of our research is to study these mechanisms using an interdisciplinary chemical biology approach.
The Hedgehog Pathway
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The Hedgehog (Hh) signaling pathway is essential to embryonic development, for stem cell maintenance, and in tissue homeostasis. Extensive research efforts have led to the identification of the main proteins involved in signal transduction. Intriguingly, all of these proteins dynamically localize to the primary cilium, and this localization is essential for signal transduction. To gain a systems-level understanding of proteins involved in this important process, we conducted a genome-wide genetic screen for genes involved in Hedgehog signal transduction. Indeed, we identified many known and novel ciliary genes as well as genes with no annotated function in Hh signal transduction - exciting leads for follow-up studies.
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Our methodology: From chemical tools to biological understanding
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Small synthetic molecules have proven to be very valuable to manipulate a biological system, as illustrated by many of the small-molecule drugs currently on the market. Chemical probes, as an extension hereof, are powerful research tools to dissect biological processes. We aim to identify novel molecules that interact with the Hedgehog pathway at different levels (i.e. by cilium formation or function or by affecting downstream effector proteins) and use them as tools to perturb the pathway in a controlled manner. Importantly, we use a combination of organic chemistry, cell biology, and genetic (screening) methodologies to elucidate the mechanism of action and intracellular target of these molecules, a particular challenge when obtaining hit compounds from phenotypic screens.
Few molecular tools to perturb and study ciliary (protein) function currently exist, and the long-term goal of our lab is to fill that gap with exciting cilium chemical biology!
Chemical Biology of Ciliary Signaling
Infrastructure
We are a Chemical Biology lab at the University of Geneva, established at the beginning of 2019. We are embedded in the Department of Organic Chemistry and the NCCR Chemical Biology and as such we have access to a state-of-the-art infrastructure for organic synthesis as well as biological experiments. We also collaborate with the screening facility ACCESS for high-content small-molecule screens.
Funding
Our current research is funded by:
