Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.01.24.525366v1?rss=1

Authors: Colozza, G., Lee, H., Merenda, A., Wu, S.-H., Catala-Bordes, A., Radaszkiewicz, T., Jordens, I., Lee, J.-H., Bamford, A.-D., Farnhammer, F., Low, T. Y., Maurice, M. M., Bryja, V., Kim, J., Koo, B.-K.

Abstract:
The mammalian intestine is one of the most rapidly self-renewing tissues, driven by actively cycling stem cells residing at the crypt bottom. Together with stromal cells, Paneth cells form a major element of the niche microenvironment that provides various growth factors to orchestrate intestinal stem cell homeostasis, such as Wnt3. With 19 family members, different Wnt ligands can selectively activate {beta}-catenin dependent (canonical) or independent (non-canonical) signaling. Here, we report that Dishevelled-associated activator of morphogenesis 1 (Daam1) and its paralogue Daam2 asymmetrically regulate canonical and non-canonical Wnt (Wnt/PCP) signaling, and their function is required for Paneth cell progenitor differentiation. We found that Daam1/2 interacts with the Wnt antagonist Rnf43, and Daam1/2 double knockout stimulates canonical Wnt signaling by preventing Rnf43-dependent endo-lysosomal degradation of the ubiquitinated Wnt receptor, Frizzled (Fzd). Moreover, single-cell RNA sequencing analysis revealed that Paneth cell differentiation is impaired by Daam1/2 depletion, as a result of defective Wnt/PCP signaling. Taken together, we identified Daam1/2 as an unexpected hub molecule coordinating both canonical and non-canonical Wnt signaling, the regulation of which is fundamental for specifying an adequate number of Paneth cells while maintaining intestinal stem cell homeostasis.

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