Laboratory of Animal Genetics and Reproduction, Research Faculty of Agriculture, Hokkaido University, Sapporo 060-8589, Japan.
Graduate School of Global Food Resources/Global Center for Food, Land and Water Resources, Hokkaido University, Sapporo, Hokkaido 060-8589, Japan.
Development. 2024 Jul 15;151(14). doi: 10.1242/dev.202639. Epub 2024 Jul 30.
The Hippo pathway plays a crucial role in cell proliferation and differentiation during tumorigenesis, tissue homeostasis and early embryogenesis. Scaffold proteins from the ezrin-radixin-moesin (ERM) family, including neurofibromin 2 (NF2; Merlin), regulate the Hippo pathway through cell polarity. However, the mechanisms underlying Hippo pathway regulation via cell polarity in establishing outer cells remain unclear. In this study, we generated artificial Nf2 mutants in the N-terminal FERM domain (L64P) and examined Hippo pathway activity by assessing the subcellular localization of YAP1 in early embryos expressing these mutant mRNAs. The L64P-Nf2 mutant inhibited NF2 localization around the cell membrane, resulting in YAP1 cytoplasmic translocation in the polar cells. L64P-Nf2 expression also disrupted the apical centralization of both large tumor suppressor 2 (LATS2) and ezrin in the polar cells. Furthermore, Lats2 mutants in the FERM binding domain (L83K) inhibited YAP1 nuclear translocation. These findings demonstrate that NF2 subcellular localization mediates cell polarity establishment involving ezrin centralization. This study provides previously unreported insights into how the orchestration of the cell-surface components, including NF2, LATS2 and ezrin, modulates the Hippo pathway during cell polarization.
Hippo 通路在肿瘤发生、组织稳态和早期胚胎发生过程中的细胞增殖和分化中起着至关重要的作用。埃兹蛋白-radixin-moesin (ERM)家族的支架蛋白，包括神经纤维瘤病 2 (NF2; Merlin)，通过细胞极性调节 Hippo 通路。然而，通过细胞极性调节 Hippo 通路在建立外细胞中的机制尚不清楚。在这项研究中，我们在 N 端 FERM 结构域（L64P）中产生了人工 Nf2 突变体，并通过评估这些突变体 mRNA 表达的早期胚胎中 YAP1 的亚细胞定位来检查 Hippo 通路活性。L64P-Nf2 突变体抑制 NF2 在细胞膜周围的定位，导致极性细胞中 YAP1 的细胞质易位。L64P-Nf2 的表达也破坏了极性细胞中 LATS2 和 ezrin 的顶端中心化。此外，在 FERM 结合域（L83K）中的 Lats2 突变体抑制了 YAP1 的核易位。这些发现表明，NF2 的亚细胞定位介导了涉及 ezrin 中心化的细胞极性建立。本研究提供了以前未报道的见解，即包括 NF2、LATS2 和 ezrin 在内的细胞表面成分的协调如何在细胞极化过程中调节 Hippo 通路。
