Bicc1 and Dicer regulate left-right patterning through post-transcriptional control of the Nodal inhibitor Dand5.
Bicc1 and Dicer regulate left-right patterning through post-transcriptional control of the Nodal inhibitor Dand5.
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DOI：
10.1038/s41467-021-25464-z
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发表时间：
2021-09-16
影响因子：
16.6
通讯作者：
Schweickert A
中科院分区：
文献类型：
--
作者：
Maerker M;Getwan M;Dowdle ME;McSheene JC;Gonzalez V;Pelliccia JL;Hamilton DS;Yartseva V;Vejnar C;Tingler M;Minegishi K;Vick P;Giraldez AJ;Hamada H;Burdine RD;Sheets MD;Blum M;Schweickert A
脊椎动物左右组织者（LRO）处的旋转纤毛产生不对称的纤毛流动，其由左侧LRO边缘处的细胞感知。钙通道Pkd 2的纤毛活性对于流量传感至关重要。这个流量信号如何被进一步处理并传递到左侧板中胚层（LPM）中的决定侧向的节点级联，这在很大程度上是未知的。我们先前表明，流量下调的Nodal抑制剂Dand 5在左感觉细胞的mRNA表达。与TGF β生长因子Gdf 3复合的共表达的Nodal的去阻遏驱动LPM Nodal级联诱导。在这里，我们表明，转录后抑制dand 5是一个中心的过程中对称性破缺的非洲爪蟾，斑马鱼和小鼠。RNA结合蛋白Bicc 1通过其3′-UTR被鉴定为dand 5和gdf 3的转录后调节因子。两个不同的Bicc 1功能dand 5 mRNA观察在前和后流动阶段，影响mRNA的稳定性或流动诱导的翻译抑制，分别。为了抑制dand 5，Bicc 1与Dicer 1合作，将两种蛋白质置于流动传感过程中。有趣的是，Bicc 1介导的dand 5 3′-UTR mRNA报告基因的翻译抑制对pkd 2有反应，这表明在对称性破坏期间，流动诱导的Pkd 2信号触发了Bicc 1介导的dand 5抑制。作者表明，纤毛驱动的纤毛流动靶点dand 5的转录后调节是青蛙、鱼和小鼠对称性破坏的核心，并由dand 5 3′UTR中的139 nt Bicc 1反应元件介导，他们提出了Pkd 2调节Bicc 1/dand 5模块的证据。
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. The authors show that post-transcriptional regulation of the cilia-driven leftward flow target dand5 is central to symmetry breakage in frog, fish and mouse and is mediated by a 139 nt Bicc1 responsive element in the dand5 3′UTR, and they present evidence that Pkd2 regulates this Bicc1/dand5 module.
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通讯作者：
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