A feedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in Caenorhabditis elegans
A feedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in Caenorhabditis elegans
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DOI：
10.1073/pnas.0908131106
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发表时间：
2009-11-03
影响因子：
11.1
通讯作者：
Ambros, Victor
中科院分区：
文献类型：
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作者：
Hammell, Christopher M.;Karp, Xantha;Ambros, Victor
动物的发育是非常稳健的;尽管有生理和环境的偶然性，但细胞的命运是以空间和时间的精确度来指定的。有利的条件导致秀丽隐杆线虫通过四个幼虫阶段（L1-L4）快速发育到生殖成虫。在不利的条件下，L2幼虫可以进入发育静止，抗应激的dauer幼虫阶段，使它们能够在完成发育之前存活很长一段时间。细胞分裂和分化事件的特定进展在幼虫阶段忠实地发生，无论动物是否经历连续或子代中断的发育。发育事件的时间模式由异时基因控制，其产物包括microRNA（miRNAs）和调节蛋白。这些蛋白质之一，即α-12核激素受体，调节某些let-7家族miRNAs的转录，并介导连续与dauer中断生活史之间的选择。在这里，我们报告了一个复杂的反馈环之间的ESTA-12和let-7家族的miRNA，涉及ESTA-12的抑制let-7家族的miRNA和配体调节的转录激活和抑制的let-7-Fam的miRNA的ESTA-12。我们建议，这个反馈回路的功能，以确保鲁棒性的细胞命运的决定，并协调细胞命运与发展停滞。
Animal development is remarkably robust; cell fates are specified with spatial and temporal precision despite physiological and environmental contingencies. Favorable conditions cause Caenorhabditis elegans to develop rapidly through four larval stages (L1-L4) to the reproductive adult. In unfavorable conditions, L2 larvae can enter the developmentally quiescent, stress-resistant dauer larva stage, enabling them to survive for prolonged periods before completing development. A specific progression of cell division and differentiation events occurs with fidelity during the larval stages, regardless of whether an animal undergoes continuous or dauer-interrupted development. The temporal patterning of developmental events is controlled by the heterochronic genes, whose products include microRNAs (miRNAs) and regulatory proteins. One of these proteins, the DAF-12 nuclear hormone receptor, modulates the transcription of certain let-7-family miRNAs, and also mediates the choice between the continuous vs. dauer-interrupted life history. Here, we report a complex feedback loop between DAF-12 and the let-7-family miRNAs involving both the repression of DAF-12 by let-7-family miRNAs and the ligand-modulated transcriptional activation and repression of the let-7-Fam miRNAs by DAF-12. We propose that this feedback loop functions to ensure robustness of cell fate decisions and to coordinate cell fate with developmental arrest.