Nuclear Poly(A)-binding Protein 1-like (PABPN1L) Mediates Cytoplasmic mRNA Decay As a Placeholder during Maternal-to-zygotic Transition

Maternal mRNA degradation is a critical event of maternal-to-zygotic transition (MZT) that determines the developmental potential of early embryos. Nuclear Poly(A)-binding proteins (PABPNs) are extensively involved in mRNA post-transcriptional regulations, but their functions in mammalian MZT has not been investigated. In this study, we identified a novel maternal-effect factor PABPN1-like (PABPN1L), rather than its ubiquitously expressed homolog PABPN1, as an RNA-binding adapter of the mammalian MZT licensing factor BTG4 which mediates maternal mRNAs clearance. Female Pabpn1l null mice produced morphologically normal oocytes but were infertile owing to early developmental arrest of the resultant embryos at the 1-to-2-cell stages without undergoing ZGA. Deletion of Pabpn1l impairs the deadenylation and degradation of a subset of BTG4-targeted maternal mRNAs during MZT. In addition to recruiting BTG4 to the mRNA 3'-poly(A) tails, PABPN1L is also required for BTG4 protein accumulation in maturing oocytes by protecting BTG4 from SCF-betaTrCP1 E3 ubiquitin ligase-mediated polyubiquitination and degradation. This study highlights a noncanonical cytoplasmic function of nuclear poly(A)-binding proteins mRNA turnover as well as its physiological importance during MZT. GV oocytes, zygotes and 2-cell embryos of WT and Pabpn1l knockout for duplicates are performed RNA sequencing.母源mRNA降解是决定早期胚胎发育潜能的母源-合子转换（maternal-to-zygotic transition, MZT）过程中的关键事件。核多聚腺苷酸结合蛋白（Nuclear Poly(A)-binding proteins, PABPNs）广泛参与mRNA的转录后调控，但其在哺乳动物MZT中的功能尚未得到研究。本研究鉴定出一种新型母源效应因子PABPN1样蛋白（PABPN1-like, PABPN1L），而非其广泛表达的同源蛋白PABPN1，其作为哺乳动物MZT许可因子BTG4的RNA结合适配器，介导母源mRNA的清除。雌性Pabpn1l基因敲除小鼠可产生形态正常的卵母细胞，但由于子代胚胎在1-2细胞阶段发生早期发育阻滞且未经历合子基因组激活（zygotic genome activation, ZGA）而导致不育。在MZT过程中，Pabpn1l基因缺失会损害BTG4靶向的部分母源mRNA的脱腺苷酸化与降解。除将BTG4招募至mRNA的3'端多聚腺苷酸尾巴外，PABPN1L还可通过保护BTG4免受SCF-betaTrCP1 E3泛素连接酶介导的多聚泛素化与降解，对成熟卵母细胞中BTG4蛋白的积累起到必需作用。本研究揭示了核多聚腺苷酸结合蛋白的非经典细胞质功能参与mRNA周转，及其在MZT过程中的生理重要性。本研究对野生型（wild type, WT）与Pabpn1l基因敲除小鼠的GV期卵母细胞、受精卵及2细胞胚胎进行了重复RNA测序实验。