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首页> 外文期刊>Development >Cell cycle arrest in node cells governs ciliogenesis at the node to break left-right symmetry.
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Cell cycle arrest in node cells governs ciliogenesis at the node to break left-right symmetry.

机译：结节细胞中的细胞周期停滞控制着结节的睫状发生，以打破左右对称性。

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Cilia at the node generate a leftward fluid flow that breaks left-right symmetry. However, the molecular mechanisms that regulate ciliogenesis at the node are largely unknown. Here, we show that the epiblast-specific deletion of the gene encoding the BMP type 1 receptor (Acvr1) compromised development of nodal cilia, which results in defects in leftward fluid flow and, thus, abnormalities in left-right patterning. Acvr1 deficiency in mouse embryonic fibroblasts (MEFs) resulted in severe defects in their quiescence-induced primary cilia. Although the induction of quiescence in wild-type MEFs leads to an increase in the level of the cyclin-dependent kinase inhibitor p27(Kip1) and to rapid p27(Kip1) phosphorylation on Ser(10), MEFs deficient in Acvr1 show a reduction in both p27(Kip1) protein levels and in p27(Kip1) Ser(10) phosphorylation. The observed defects in cilium development were rescued by the introduction of p27(Kip1) into Acvr1-deficient MEFs, implying that BMP signaling positively controls p27(Kip1) stability in the G0 phase via p27(Kip1) Ser(10) phosphorylation, which is a prerequisite for induction of primary cilia. Importantly, in control embryos, p27(Kip1) protein is clearly present and strongly phosphorylated on Ser(10) in cells on the quiescent ventral surface of the node. By contrast, the corresponding cells in the node of Acvr1 mutant embryos were proliferative and showed a dramatic attenuation in both p27(Kip1) protein levels and phosphorylation on Ser(10). Our data suggest that cell quiescence controlled by BMP signaling via ACVR1 is required for transient formation of nodal cilia, and provide insight into the fundamental question of how the node represents the mechanistic `node' that regulates the development of left-right symmetry in vertebrates.
机译：节点处的纤毛产生破坏了左右对称性的向左流体流。但是，调节结节纤毛发生的分子机制尚不清楚。在这里，我们显示了编码BMP 1型受体（Acvr1）的基因的表皮细胞特异性缺失损害了节点纤毛的发育，这导致了左侧流体流动的缺陷，并因此导致了左右模式的异常。小鼠胚胎成纤维细胞（MEF）中Acvr1缺乏症导致其静止诱导的初级纤毛严重缺陷。尽管在野生型MEF中诱导静止会导致细胞周期蛋白依赖性激酶抑制剂p27（Kip1）的水平增加并导致Ser（10）上的快速p27（Kip1）磷酸化，但缺乏Acvr1的MEF的减少p27（Kip1）蛋白质水平和p27（Kip1）Ser（10）磷酸化均如此。通过将p27（Kip1）引入到Acvr1缺陷型MEF中来挽救观察到的纤毛发育缺陷，这意味着BMP信号通过p27（Kip1）Ser（10）磷酸化在G0相中积极控制p27（Kip1）稳定性。诱导原发纤毛的先决条件。重要的是，在对照胚胎中，p27（Kip1）蛋白清楚地存在，并且在节点静止腹侧表面的细胞中的Ser（10）上强烈磷酸化。相比之下，Acvr1突变体胚胎的节点中的相应细胞是增殖性的，并且在p27（Kip1）蛋白水平和Ser（10）的磷酸化上均表现出极大的衰减。我们的数据表明，通过结节纤毛的瞬时形成需要通过ACVR1的BMP信号控制的细胞静止，并提供了对节点如何代表调节脊椎动物左右对称性发展的机制“节点”的基本问题的见解。

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