Department of Stem Cell Biology and Regenerative Medicine, Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, 300071, Tianjin, China.
Nat Commun. 2018 Jan 26;9(1):401. doi: 10.1038/s41467-017-02720-9.
Kruppel-like factor 4 (Klf4) is a zinc-finger-containing protein that plays a critical role in diverse cellular physiology. While most of these functions attribute to its role as a transcription factor, it is postulated that Klf4 may play a role other than transcriptional regulation. Here we demonstrate that Klf4 loss in neural progenitor cells (NPCs) leads to increased neurogenesis and reduced self-renewal in mice. In addition, Klf4 interacts with RNA-binding protein Staufen1 (Stau1) and RNA helicase Ddx5/17. They function together as a complex to maintain NPC self-renewal. We report that Klf4 promotes Stau1 recruitment to the 3'-untranslated region of neurogenesis-associated mRNAs, increasing Stau1-mediated mRNA decay (SMD) of these transcripts. Stau1 depletion abrogated SMD of target mRNAs and rescued neurogenesis defects in Klf4-overexpressing NPCs. Furthermore, Ddx5/17 knockdown significantly blocked Klf4-mediated mRNA degradation. Our results highlight a novel molecular mechanism underlying stability of neurogenesis-associated mRNAs controlled by the Klf4/Ddx5/17/Stau1 axis during mammalian corticogenesis.
Kruppel 样因子 4（Klf4）是一种含锌指的蛋白质，在多种细胞生理中发挥着关键作用。虽然这些功能大多归因于其作为转录因子的作用，但据推测 Klf4 可能具有转录调控以外的作用。在这里，我们证明 Klf4 在神经祖细胞（NPC）中的缺失会导致小鼠神经发生增加和自我更新减少。此外，Klf4 与 RNA 结合蛋白 Staufen1（Stau1）和 RNA 解旋酶 Ddx5/17 相互作用。它们作为一个复合物共同维持 NPC 的自我更新。我们报告称，Klf4 促进 Stau1 募集到与神经发生相关的 mRNA 的 3'-非翻译区，增加这些转录物的 Stau1 介导的 mRNA 衰减（SMD）。Stau1 耗竭消除了靶 mRNA 的 SMD，并挽救了 Klf4 过表达 NPC 中的神经发生缺陷。此外，Ddx5/17 的敲低显著阻止了 Klf4 介导的 mRNA 降解。我们的研究结果突出了一个新的分子机制，即在哺乳动物皮质发生过程中，Klf4/Ddx5/17/Stau1 轴控制与神经发生相关的 mRNA 的稳定性。
