Swiss Federal Institute of Technology Zurich, IMHS, Chair of RNAi and Genome Integrity, Zurich, Switzerland.
Swiss Federal Institute of Technology Zurich, IMHS, Chair of RNAi and Genome Integrity, Zurich, Switzerland; Life Science Zurich Graduate School, University of Zürich, Zurich, Switzerland.
Stem Cell Reports. 2018 Feb 13;10(2):461-476. doi: 10.1016/j.stemcr.2017.12.023. Epub 2018 Jan 26.
In mouse, although four Argonaute (AGO) proteins with partly overlapping functions in small-RNA pathways exist, only Ago2 deficiency causes embryonic lethality. To investigate the role of AGO2 during mouse early development, we generated Ago2-deficient mouse embryonic stem cells (mESCs) and performed a detailed characterization of their differentiation potential. Ago2 disruption caused a global reduction of microRNAs, which resulted in the misregulation of only a limited number of transcripts. We demonstrated, both in vivo and in vitro, that AGO2 is dispensable for the embryonic germ-layer formation. However, Ago2-deficient mESCs showed a specific defect during conversion into extra-embryonic endoderm cells. We proved that this defect is cell autonomous and can be rescued by both a catalytically active and an inactive Ago2, but not by Ago2 deprived of its RNA binding capacity or by Ago1 overexpression. Overall, our results suggest a role for AGO2 in stem cell differentiation.
在小鼠中，尽管存在四种 Argonaute（AGO）蛋白，它们在小 RNA 途径中具有部分重叠的功能，但只有 Ago2 缺陷会导致胚胎致死。为了研究 AGO2 在小鼠早期发育中的作用，我们生成了 Ago2 缺陷型小鼠胚胎干细胞（mESCs），并对其分化潜能进行了详细表征。Ago2 的缺失导致 microRNAs 的全面减少，这仅导致少数转录物的失调。我们证明，无论是在体内还是体外，AGO2 对于胚胎生殖层的形成都是可有可无的。然而，Ago2 缺陷型 mESCs 在转化为胚胎外内胚层细胞时表现出特定的缺陷。我们证明，这种缺陷是细胞自主性的，可以通过具有催化活性和无活性的 Ago2 来挽救，但不能通过缺乏 RNA 结合能力的 Ago2 或 Ago1 过表达来挽救。总的来说，我们的结果表明 AGO2 在干细胞分化中起作用。
