University of Hohenheim, Institute of Biology, Department of Zoology, Stuttgart, Germany.
University of Zurich, Institute of Anatomy, Zurich, Switzerland.
Nat Commun. 2021 Sep 16;12(1):5482. doi: 10.1038/s41467-021-25464-z.
Rotating cilia at the vertebrate left-right organizer (LRO) generate an asymmetric leftward flow, which is sensed by cells at the left LRO margin. Ciliary activity of the calcium channel Pkd2 is crucial for flow sensing. How this flow signal is further processed and relayed to the laterality-determining Nodal cascade in the left lateral plate mesoderm (LPM) is largely unknown. We previously showed that flow down-regulates mRNA expression of the Nodal inhibitor Dand5 in left sensory cells. De-repression of the co-expressed Nodal, complexed with the TGFß growth factor Gdf3, drives LPM Nodal cascade induction. Here, we show that post-transcriptional repression of dand5 is a central process in symmetry breaking of Xenopus, zebrafish and mouse. The RNA binding protein Bicc1 was identified as a post-transcriptional regulator of dand5 and gdf3 via their 3'-UTRs. Two distinct Bicc1 functions on dand5 mRNA were observed at pre- and post-flow stages, affecting mRNA stability or flow induced translational inhibition, respectively. To repress dand5, Bicc1 co-operates with Dicer1, placing both proteins in the process of flow sensing. Intriguingly, Bicc1 mediated translational repression of a dand5 3'-UTR mRNA reporter was responsive to pkd2, suggesting that a flow induced Pkd2 signal triggers Bicc1 mediated dand5 inhibition during symmetry breakage.
脊椎动物左右组织者（LRO）的旋转纤毛产生不对称的向左流动，这被左 LRO 边缘的细胞感知。钙通道 Pkd2 的纤毛活动对于流动感应至关重要。这个流动信号如何进一步被处理并传递到左侧侧板中胚层（LPM）中的决定左右性的 Nodal 级联，在很大程度上是未知的。我们之前表明，流动下调了左侧感觉细胞中 Nodal 抑制剂 Dand5 的 mRNA 表达。共表达的 Nodal 的去抑制，与 TGFß 生长因子 Gdf3 复合，驱动 LPM Nodal 级联诱导。在这里，我们表明，在爪蟾、斑马鱼和小鼠中，dand5 的转录后抑制是对称性破缺的核心过程。RNA 结合蛋白 Bicc1 被鉴定为通过其 3'-UTR 对 dand5 和 gdf3 的转录后调节剂。在预流和后流阶段观察到 Bicc1 对 dand5 mRNA 的两种不同功能，分别影响 mRNA 稳定性或流动诱导的翻译抑制。为了抑制 dand5，Bicc1 与 Dicer1 合作，使这两种蛋白都参与到流动感应过程中。有趣的是，Bicc1 介导的 dand5 3'-UTR mRNA 报告基因的翻译抑制对 pkd2 有反应，这表明流动诱导的 Pkd2 信号在对称性破缺期间触发 Bicc1 介导的 dand5 抑制。
