Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA
Development. 2019 Nov 6;146(21):dev183111. doi: 10.1242/dev.183111.
MicroRNAs target complementary mRNAs for degradation or translational repression, reducing or preventing protein synthesis. In , the transcription factor HBL-1 (Hunchback-like 1) promotes early larval (L2)-stage cell fates, and the family microRNAs temporally downregulate HBL-1 to enable the L2-to-L3 cell-fate progression. In parallel to -family microRNAs, the conserved RNA-binding protein LIN-28 and its downstream gene also act upstream of HBL-1 in regulating the L2-to-L3 cell-fate progression. The molecular function of LIN-46, and how the pathway regulates HBL-1, are not understood. Here, we report that the regulation of HBL-1 by the pathway is independent of the / microRNA complementary sites (LCSs) in the 3'UTR, and involves stage-specific post-translational regulation of HBL-1 nuclear accumulation. We find that LIN-46 is necessary and sufficient to prevent nuclear accumulation of HBL-1. Our results illuminate that robust progression from L2 to L3 cell fates depends on the combination of two distinct modes of HBL-1 downregulation: decreased synthesis of HBL-1 via -family microRNA activity, and decreased nuclear accumulation of HBL-1 via action of the - pathway.
MicroRNAs 通过靶向互补的 mRNAs 进行降解或翻译抑制，从而减少或阻止蛋白质合成。在 中，转录因子 HBL-1（Hunchback-like 1）促进早期幼虫（L2）阶段的细胞命运，而 家族 microRNAs 则暂时下调 HBL-1，以使 L2 到 L3 细胞命运进程。与 家族 microRNAs 平行的是，保守的 RNA 结合蛋白 LIN-28 及其下游基因 也在上游调节 HBL-1 的 L2 到 L3 细胞命运进程。LIN-46 的分子功能以及 途径如何调节 HBL-1 尚不清楚。在这里，我们报告说， 途径对 HBL-1 的调控不依赖于 3'UTR 中的 / microRNA 互补位点（LCSs），并且涉及 HBL-1 核积累的特定阶段的翻译后调控。我们发现 LIN-46 对于防止 HBL-1 的核积累是必需且充分的。我们的结果阐明了从 L2 到 L3 细胞命运的稳健进展取决于两种不同的 HBL-1 下调模式的组合：通过 家族 microRNA 活性降低 HBL-1 的合成，以及通过 途径的作用降低 HBL-1 的核积累。
