Intestinal Paneth cell differentiation relies on asymmetric regulation of Wnt signaling by Daam1/2

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.

doi:10.1101/2023.01.24.525366

bioRxiv · 10.1101/2023.01.24.525366

Intestinal Paneth cell differentiation relies on asymmetric regulation of Wnt signaling by Daam1/2

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.

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Abstract

The mammalian intestine is one of the most rapidly self-renewing tissues, driven by actively cycling stem cells residing at the crypt bottom1,2. 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 Wnt33. With 19 family members, different Wnt ligands can selectively activate {beta}-catenin dependent (canonical) or independent (non-canonical) signaling4,5. 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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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.. 2023-01-25. Intestinal Paneth cell differentiation relies on asymmetric regulation of Wnt signaling by Daam1/2. https://doi.org/10.1101/2023.01.24.525366

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