LIN-14 Inhibition of LIN-12 Contributes to Precision and Timing of C. elegans Vulval Fate Patterning
LIN-14 Inhibition of LIN-12 Contributes to Precision and Timing of C. elegans Vulval Fate Patterning
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DOI：
10.1016/j.cub.2010.09.055
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发表时间：
2010-10-26
期刊：
影响因子：
9.2
通讯作者：
Greenwald, Iva
中科院分区：
文献类型：
--
作者：
Li, Ji;Greenwald, Iva
对线虫外阴发育的研究阐明了细胞命运规范的潜在机制并阐明了细胞间信号传导通路[1]。外阴前体细胞 (VPC) 在 L3 阶段由 EGFR-Ras-MAPK 介导的诱导信号和 LIN-12/Notch 介导的横向信号形成空间图案。由于这些路径之间的串扰，该模式既精确又稳健 [2] [3]。信号传导也在时间上受到调节，因为空间模式通路的组成性激活不会改变 VPC 命运规范的时间 [4, 5]。异时基因，包括 microRNA lin-4 及其靶标 lin-14，构成了在不同情况下使用的时间控制机制 [6-8]。我们发现 lin-4 通过 lin-14 特异性控制 LIN-12/Notch 的活性，但不影响其他已知靶标，并且持久的 lin-14 会阻断 LIN-12 活性，而不干扰 LIN-12/Notch 信号转导的关键事件。在L2阶段，有足够的lin-14活性来抑制组成型lin-12。我们的结果表明 lin-4 和 lin-14 通过 LIN-12 的时间门控有助于空间模式。我们提出，在L2阶段，lin-14为LIN-12激活设定了一个高阈值，以帮助防止附近其他细胞中表达的配体过早激活LIN-12，从而有助于VPC命运模式的精确性和稳健性。
Studies of C. elegans vulval development have illuminated mechanisms underlying cell fate specification and elucidated intercellular signaling pathways [1]. The vulval precursor cells (VPCs) are spatially patterned during the L3 stage by the EGFR-Ras-MAPK-mediated inductive signal and the LIN-12/Notch-mediated lateral signal. The pattern is both precise and robust [2] because of crosstalk between these pathways [3]. Signaling is also regulated temporally, because constitutive activation of the spatial patterning pathways does not alter the timing of VPC fate specification [4, 5]. The heterochronic genes, including the microRNA lin-4 and its target lin-14, constitute a temporal control mechanism used in different contexts [6-8]. We find that lin-4 specifically controls the activity of LIN-12/Notch through lin-14, but not other known targets, and that persistent lin-14 blocks LIN-12 activity without interfering with the key events of LIN-12/Notch signal transduction. In the L2 stage, there is sufficient lin-14 activity to inhibit constitutive lin-12. Our results suggest that lin-4 and lin-14 contribute to spatial patterning through temporal gating of LIN-12. We propose that in the L2 stage, lin-14 sets a high threshold for LIN-12 activation to help prevent premature activation of LIN-12 by ligands expressed in other cells in the vicinity, thereby contributing to the precision and robustness of VPC fate patterning.