Neddylation Inhibition Causes Impaired Mouse Embryo Quality and Blastocyst Hatching Failure Through Elevated Oxidative Stress and Reduced IL-1β

Abstract

Mammalian blastocyst hatching is an essential prerequisite for successful embryo implantation. As the rate-limiting step of current assisted reproductive technology, understanding the key factors regulating blastocyst hatching would be significantly helpful to improve the performance of the assisted reproductive practice. In early embryo development, the fine-tuned elimination of maternal materials and the balanced protein turnover are inevitable for the competent to hatch and implant into endometrium. Neddylation, a ubiquitination-like protein modification, has been shown to be involved in oocyte maturation and early embryo development. In this study, aiming to discover an unknown role of neddylation in the blastocyst hatching process, we provided functional evidence of neddylation in mammalian embryo quality and blastocyst hatching. Treatment with MLN4924, a specific neddylation inhibitor, lowered the embryo quality and dramatically reduced the hatching rate in mouse blastocysts. The transcriptional profile showed the upregulation of oxidative stress-related genes and aberrant expression of immune-related genes. The elevated oxidative stress was validated by qPCR and markers of apoptosis, DNA damage, reactive oxygen species, and cytoskeleton. Moreover, we found the secreted IL-1β level was reduced in an NF-κB-independent manner, leading to the final poor embryo quality and blastocyst hatching failure. This is the first report of neddylation being of great importance in the mammalian blastocyst hatching process. Further investigations uncovering more detailed molecular mechanisms of neddylation regulation in blastocyst hatching would greatly promote not only the understanding of this crucial biological process but also the clinical application in reproductive centers.

GRP78 acts as a cAMP/PKA signaling modulator through the MC4R pathway in porcine embryonic development

“…Previous studies have used blastocyst diameter and total cell number to assess blastocyst quality, 29,30 and oxidative stress is also an indicator of blastocyst quality 31,32 ; therefore, these parameters were examined to determine blastocyst quality. Studies have shown that blastocyst quality is critical for embryonic stem cell production and other related applications 33,34 .…”

Inhibition of neddylation causes early developmental arrestment in mouse embryo because of the zygotic genome activation failure

“…In addition, inhibition of this pathway in bovine embryos will lead to delayed embryonic development and reduced blastocyst formation rate [12]. In our earlier research, we discovered that neddylation suppression results in poorer mouse embryo quality and unsuccessful blastocyst hatching [13]. Nonetheless, the detailed molecular mechanism of neddylation governing embryonic development has not yet been understood.…”