Induction of Autophagy Promotes Preattachment Development of Bovine Embryos by Reducing Endoplasmic Reticulum Stress1

Abstract

The coupling of autophagy and endoplasmic reticulum (ER) stress has been implicated in a variety of biological processes; however, little is known regarding the involvement of the autophagy/ER stress pathway in early embryogenesis or the underlying mechanism(s). Here, we showed that the developmental competence of in vitro-produced (IVP) bovine embryos was highly dependent on the autophagy/ER stress balance. Although relative abundances of autophagy-associated gene transcripts, including LC3, Atg5, and Atg7 transcripts, were high in oocytes and throughout the early stages of preattachment development, extensive autophagosome formation was only detected in fertilized embryos. Using an inducer and inhibitor of autophagy, we showed that transient elevation of autophagic activity during early preattachment development greatly increased the blastocyst development rate, trophectoderm cell numbers, and blastomere survival; these same parameters were reduced by both inhibition and prolonged induction of autophagy. Interestingly, the induction of autophagy reduced ER stress and associated damage, while the developmental defects in autophagy-inhibited embryos were significantly alleviated by ER stress inhibitor treatment, indicating that autophagy is a negative regulator of ER stress in early embryos. Collectively, these results suggest that early embryogenesis of IVP bovine embryos depends on an appropriate balance between autophagy and ER stress. These findings may increase our understanding of important early developmental events by providing compelling evidence concerning the tight association between autophagy and ER stress, and may contribute to the development of strategies for the production of IVP bovine blastocysts with high developmental competence.

Endoplasmic Reticulum Stress Promotes Autophagy and Apoptosis and Reduces Chemotherapy Resistance in Mutant p53 Lung Cancer Cells

“…The cancer cells had reduced apoptosis and increased drug resistance. LC3-II/LC3-I, Atg7, and Atg5 are autophagy-related gene transcripts [39]. Located on the ER cytoplasmic surface, caspase-12 is a key biomarker of ERS-specific apoptosis [40, 41].…”

Autophagy in the placenta

“…The dynamic protein turnover by autophagy at this stage may be a critical determinant for normal embryonic development. In a study by Song et al [86], treatment of bovine zygotes with rapamycin for transient elevation of autophagic activity during early preattachment development greatly increased the blastocyst development rate, trophectoderm cell numbers, and blastomere survival; these same parameters were reduced by both inhibition and prolonged induction of autophagy. After this initial induction during the transition from oocyte to zygote, there is a gradual decrease in autophagy-related gene transcription through the morula and blastocyst stages [79].…”

Stress signaling in mammalian oocytes and embryos: a basis for intervention and improvement of outcomes

“…With mild or short-lived stress, early ERSS events may provide the capacity for the cell to recover, for example by inhibiting protein translation and any further accumulation of unfolded proteins, increasing expression of chaperones, and increasing expression of ERAD components to clear the unfolded protein. Activation of autophagy allows the removal of damaged proteins or cell structures, and factors that activate autophagy can inhibit cell death upon ERSS activation (Kapuy, et al, 2014, Song, et al, 2012, Tirupathi Pichiah, et al, 2011). …”