Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Dev Cell. 2023 Aug 21;58(16):1447-1461.e6. doi: 10.1016/j.devcel.2023.06.002. Epub 2023 Jul 5.
Left-dominant [Ca] elevation on the left margin of the ventral node furnishes the initial laterality of mouse embryos. It depends on extracellular leftward fluid flow (nodal flow), fibroblast growth factor receptor (FGFR)/sonic hedgehog (Shh) signaling, and the PKD1L1 polycystin subunit, of which interrelationship is still elusive. Here, we show that leftward nodal flow directs PKD1L1-containing fibrous strands and facilitates Nodal-mediated [Ca] elevation on the left margin. We generate KikGR-PKD1L1 knockin mice in order to monitor protein dynamics with a photoconvertible fluorescence protein tag. By imaging those embryos, we have identified fragile meshwork being gradually transferred leftward involving pleiomorphic extracellular events. A portion of the meshwork finally bridges over the left nodal crown cells in an FGFR/Shh-dependent manner. As PKD1L1 N-term is predominantly associated with Nodal on the left margin and that PKD1L1/PKD2 overexpression significantly augments cellular Nodal sensitivity, we propose that leftward transfer of polycystin-containing fibrous strands determines left-right asymmetry in developing embryos.
左侧优势[Ca]在腹节神经节左侧边缘的升高提供了小鼠胚胎最初的左右侧分化。这取决于细胞外的左侧液流（神经节流）、成纤维细胞生长因子受体（FGFR）/刺猬信号（Shh）信号以及多囊蛋白 1 样 1（PKD1L1）多聚蛋白亚基，它们之间的相互关系仍不清楚。在这里，我们表明，左侧神经节流指导含有 PKD1L1 的纤维束，并促进左侧 Nodal 介导的[Ca]升高。我们生成了 KikGR-PKD1L1 基因敲入小鼠，以便用光转化荧光蛋白标签监测蛋白质动力学。通过对这些胚胎进行成像，我们已经确定了脆弱的网格结构逐渐向左侧转移，涉及多种细胞外事件。网格的一部分最终以 FGFR/Shh 依赖的方式跨越左侧神经节冠细胞。由于 PKD1L1 N 端主要与左侧神经节上的 Nodal 相关，并且 PKD1L1/PKD2 的过表达显著增加了细胞对 Nodal 的敏感性，因此我们提出，含有多囊蛋白的纤维束的左侧转移决定了发育中胚胎的左右不对称性。
