Nuclearporin subcomplex Nup98/Rae1 is vital for maternal-to-zygotic transition during early embryonic development

Abstract

The Nup98/Rae1 nuclear pore subcomplex, a critical mediator of nucleocytoplasmic transport, orchestrates fundamental cellular processes including transcriptional regulation, mRNA surveillance, and mitotic fidelity. However, its functional significance during early embryogenesis remains incompletely understood. In this study, we employed an in vitro embryo culture system combined with embryo electroporation-mediated interference to investigate the role of Nup98/Rae1 in early mouse embryos. Our results revealed that Nup98/Rae1 deficiency led to delayed embryonic progression and a significant decline in blastocyst formation rates. Transcriptomic analysis using SMART-seq2 in two-cell stage embryos revealed that Nup98/Rae1 modulates global gene expression, particularly within pathways governing RNA splicing, protein catabolism, and the DNA damage response. Integration of transcriptomic data with established databases further confirmed that Nup98/Rae1 is indispensable for zygotic genome activation and maternal mRNA clearance-key events in the maternal-to-zygotic transition. Moreover, quantitative immunofluorescence analysis demonstrated that loss of Nup98/Rae1 resulted in heightened DNA damage and reduced H3K27ac levels. Additionally, the increased mRNA expression of apoptosis-related markers BAX and CASPASE3, alongside positive TUNEL staining, indicated the induction of early apoptosis. Immunostaining for Sox2 and Cdx2 revealed a defective inner cell mass development, highlighting the detrimental impact of Nup98/Rae1 on cell fate specification. Collectively, these findings indicate that Nup98/Rae1 deficiency disrupts maternal mRNA degradation, impairs zygotic genome activation, alters histone modifications, induces genomic instability, and ultimately compromises early embryonic development by triggering apoptosis.

Keywords: Early embryonic development; Histone modification; Nup98; Rae1; Zygotic genome activation.