Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), 1030 Vienna, Austria.
Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseong-gu, Daejeon 34126, Republic of Korea.
Sci Adv. 2023 Nov 24;9(47):eadh9673. doi: 10.1126/sciadv.adh9673.
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.
哺乳动物的肠道是自我更新最快的组织之一，由位于隐窝底部的干细胞驱动。潘氏细胞形成了生态位微环境的主要组成部分，提供各种生长因子来协调肠道干细胞的稳态，如 Wnt3。不同的 Wnt 配体可以选择性地激活β-连环蛋白依赖性（经典）或非依赖性（非经典）信号转导。在这里，我们报告 Dishevelled 相关形态发生激活因子 1（Daam1）及其同源物 Daam2 不对称地调节经典和非经典 Wnt（Wnt/PCP）信号。Daam1/2 与 Wnt 抑制剂 RNF43 相互作用，并且 Daam1/2 双敲除通过阻止 RNF43 依赖性降解 Wnt 受体 Frizzled（Fzd）来刺激经典 Wnt 信号。单细胞 RNA 测序分析显示，由于 Wnt/PCP 信号的缺陷，潘氏细胞分化受损。Daam1/2 作为一种意想不到的枢纽分子，协调经典和非经典 Wnt，对指定足够数量的潘氏细胞至关重要。
