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.

脊椎动物左右组织器 (LRO) 处的旋转纤毛产生不对称的向左流动，左侧 LRO 边缘的细胞可以感知到这种流动。钙通道 Pkd2 的纤毛活动对于流量传感至关重要。这种流动信号如何被进一步处理并传递到左侧板中胚层 (LPM) 中决定侧向性的节点级联在很大程度上是未知的。我们之前表明，流动下调左感觉细胞中 Nodal 抑制剂 Dand5 的 mRNA 表达。与 TGFß 生长因子 Gdf3 复合的共表达 Nodal 的去抑制，驱动 LPM Nodal 级联诱导。在这里，我们表明dand5的转录后抑制是非洲爪蟾对称性破坏的中心过程、 斑马鱼和鼠标。RNA 结合蛋白 Bicc1通过其 3'-UTR被鉴定为dand5和gdf3的转录后调节因子。在流动前和流动后阶段观察到dand5 mRNA上的两种不同的 Bicc1 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，将两种蛋白质置于流量传感过程中。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 信号在对称性破坏期间触发了 Bicc1 介导的 dand5抑制。