RNA 解旋酶 DDX6 通过 miRNA 介导的基因沉默来抑制 BMP 信号的异常抑制，从而控制早期小鼠胚胎发生。
The RNA helicase DDX6 controls early mouse embryogenesis by repressing aberrant inhibition of BMP signaling through miRNA-mediated gene silencing.
机构信息
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
Mammalian Development Laboratory, Department of Gene Function and Phenomics, National Institute of Genetics, Mishima, Japan.
出版信息
PLoS Genet. 2022 Oct 5;18(10):e1009967. doi: 10.1371/journal.pgen.1009967. eCollection 2022 Oct.
The evolutionarily conserved RNA helicase DDX6 is a central player in post-transcriptional regulation, but its role during embryogenesis remains elusive. We here show that DDX6 enables proper cell lineage specification from pluripotent cells by analyzing Ddx6 knockout (KO) mouse embryos and employing an in vitro epiblast-like cell (EpiLC) induction system. Our study unveils that DDX6 is an important BMP signaling regulator. Deletion of Ddx6 causes the aberrant upregulation of the negative regulators of BMP signaling, which is accompanied by enhanced expression of Nodal and related genes. Ddx6 KO pluripotent cells acquire higher pluripotency with a strong inclination toward neural lineage commitment. During gastrulation, abnormally expanded Nodal and Eomes expression in the primitive streak likely promotes endoderm cell fate specification while inhibiting mesoderm differentiation. We also genetically dissected major DDX6 pathways by generating Dgcr8, Dcp2, and Eif4enif1 KO models in addition to Ddx6 KO. We found that the miRNA pathway mutant Dgcr8 KO phenocopies Ddx6 KO, indicating that DDX6 mostly works along with the miRNA pathway during early development, whereas its P-body-related functions are dispensable. Therefore, we conclude that DDX6 prevents aberrant upregulation of BMP signaling inhibitors by participating in miRNA-mediated gene silencing processes. Overall, this study delineates how DDX6 affects the development of the three primary germ layers during early mouse embryogenesis and the underlying mechanism of DDX6 function.
进化上保守的 RNA 解旋酶 DDX6 是转录后调控的核心分子，但它在胚胎发生过程中的作用仍不清楚。通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 允许多能细胞通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 允许多能细胞通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 允许多能细胞通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 允许多能细胞通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 允许多能细胞通过分析 Ddx6 敲除（KO）小鼠胚胎和使用体外类上胚层细胞（EpiLC）诱导系统，我们发现 DDX6 允许多能细胞specification from pluripotent cells by analyzing Ddx6 knockout (KO) mouse embryos and employing an in vitro epiblast-like cell (EpiLC) induction system. Our study unveils that DDX6 is an important BMP signaling regulator. Deletion of Ddx6 causes the aberrant upregulation of the negative regulators of BMP signaling, which is accompanied by enhanced expression of Nodal and related genes. Ddx6 KO pluripotent cells acquire higher pluripotency with a strong inclination toward neural lineage commitment. During gastrulation, abnormally expanded Nodal and Eomes expression in the primitive streak likely promotes endoderm cell fate specification while inhibiting mesoderm differentiation. We also genetically dissected major DDX6 pathways by generating Dgcr8, Dcp2, and Eif4enif1 KO models in addition to Ddx6 KO. We found that the miRNA pathway mutant Dgcr8 KO phenocopies Ddx6 KO, indicating that DDX6 mostly works along with the miRNA pathway during early development, whereas its P-body-related functions are dispensable. Therefore, we conclude that DDX6 prevents aberrant upregulation of BMP signaling inhibitors by participating in miRNA-mediated gene silencing processes. Overall, this study delineates how DDX6 affects the development of the three primary germ layers during early mouse embryogenesis and the underlying mechanism of DDX6 function.
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