Intestinal Paneth cell differentiation relies on asymmetric regulation of Wnt signaling by Daam1/2
Gabriele Colozza, Heetak Lee, Alessandra Merenda, Szu-Hsien Sam Wu, Andrea Català-Bordes, Tomasz Radaszkiewicz, Ingrid Jordens, Ji‐Hyun Lee, Aileen-Diane Bamford, Fiona Farnhammer, Teck Yew Low, Madelon M. Maurice, Vı́tězslav Bryja, Jihoon Kim, Bon‐Kyoung Koo
Abstract
The mammalian intestine is one of the most rapidly self-renewing tissues, driven by stem cells residing at the crypt bottom. Paneth cells form a major element of the niche microenvironment providing various growth factors to orchestrate intestinal stem cell homeostasis, such as Wnt3. Different Wnt ligands can selectively activate β-catenin-dependent (canonical) or -independent (noncanonical) signaling. Here, we report that the Dishevelled-associated activator of morphogenesis 1 (Daam1) and its paralogue Daam2 asymmetrically regulate canonical and noncanonical Wnt (Wnt/PCP) signaling. Daam1/2 interacts with the Wnt inhibitor RNF43, and Daam1/2 double knockout stimulates canonical Wnt signaling by preventing RNF43-dependent degradation of the Wnt receptor, Frizzled (Fzd). Single-cell RNA sequencing analysis revealed that Paneth cell differentiation is impaired by Daam1/2 depletion because of defective Wnt/PCP signaling. Together, we identified Daam1/2 as an unexpected hub molecule coordinating both canonical and noncanonical Wnt, which is fundamental for specifying an adequate number of Paneth cells.