Wnt proteins are members of a conserved family of signaling molecules that play a central role in development, adult tissue homeostasis and disease. In the past decade, much attention has been focused on how binding of Wnt to its receptors LRP6 and Frizzled triggers the expression of specific target genes and we now have a detailed understanding of the so-called canonical Wnt/beta-catenin pathway that is involved. Wnt proteins also activate other signaling pathways and especially the signaling mechanisms that control Wnt dependent cell and axon migration are still mostly unexplored. Also, it is still largely unknown how the lipid-modified Wnt protein is secreted from producing cells and how it forms the highly reproducible concentration gradients that are essential for the correct patterning of developing tissues. We use the nematode C. elegans to study these two key questions:
Mechanism of Wnt secretion
We are taking a combined genetic and cell biological approach to study the mechanism of Wnt secretion. Central to our studies is the Wnt binding protein Wntless (Wls), which shuttles between the Golgi and the plasma membrane to mediate Wnt secretion. We have performed genome-wide RNAi screens in C. elegans to identify regulators of Wls trafficking, which we are studying in C. elegans and in mammalian tissue-culture cells.
Wnt signaling and cell migration
We are using the left-right asymmetric migration of the Q neuroblasts in C. elegans as a model system to study Wnt controlled cell migration. We have two main questions: First, how do cells choose between canonical and non-canonical Wnt pathways? We are addressing this question using genetics, live cell imaging and single mRNA FISH of Wnt receptors and pathway components. Second, we are genetically dissecting the non-canonical Wnt signaling pathway that controls anterior migration of the Q neuroblast descendants.
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