Li Xiaoyong, Tian Geng, Wu Ji
Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Renji Hospital, School of Medicine, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.
Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, China.
Front Cell Dev Biol. 2021 Apr 12;9:640402. doi: 10.3389/fcell.2021.640402. eCollection 2021.
Circular RNAs (circRNAs) play important roles in the self-renewal of stem cells. However, their significance and regulatory mechanisms in female germline stem cells (FGSCs) are largely unknown. Here, we identified an -methyladenosine (mA)-modified circRNA, circGFRα1, which is highly abundant in mouse ovary and stage-specifically expressed in mouse FGSC development. Knockdown of circGFRα1 in FGSCs significantly reduced their self-renewal. In contrast, overexpression of circGFRα1 enhanced FGSC self-renewal. Mechanistically, circGFRα1 promotes FGSC self-renewal by acting as a competing endogenous RNA (ceRNA) that sponges miR-449, leading to enhanced GFRα1 expression and activation of the glial cell derived neurotrophic factor (GDNF) signaling pathway. Furthermore, circGFRα1 acts as a ceRNA based on METTL14-mediated cytoplasmic export through the GGACU motif. Our study should help to understand the mechanisms regulating germ cell development, add new evidence on the mechanism of action of circRNA, and deepen our understanding of the development of FGSCs.
环状RNA（circRNAs）在干细胞自我更新中发挥重要作用。然而，它们在雌性生殖系干细胞（FGSCs）中的意义和调控机制在很大程度上尚不清楚。在此，我们鉴定出一种N6-甲基腺苷（m6A）修饰的环状RNA，即circGFRα1，其在小鼠卵巢中高度丰富，并在小鼠FGSC发育过程中呈现阶段特异性表达。在FGSCs中敲低circGFRα1会显著降低其自我更新能力。相反，circGFRα1的过表达增强了FGSC的自我更新。从机制上讲，circGFRα1通过作为竞争性内源RNA（ceRNA）发挥作用，吸附miR-449，从而导致GFRα1表达增强以及胶质细胞源性神经营养因子（GDNF）信号通路的激活，进而促进FGSC自我更新。此外，circGFRα1基于METTL14介导的通过GGACU基序的细胞质输出而作为ceRNA发挥作用。我们的研究应有助于理解调控生殖细胞发育的机制，为circRNA的作用机制增添新证据，并加深我们对FGSCs发育的理解。
