**3. Autophagy in Reproduction**

Functions of oocytes, including ovulation, fertilization, and implantation, were not a ffected by autophagy inhibition in the ovary-specific Beclin1 knockout mouse model [15]. Atg7 was found to protect against ovarian follicle loss in germ cell-specific Atg7 knockout mice [16]. This suggests that Atg proteins are more involved in downstream—rather than upstream—regulation of the ovarian reserve of primordial follicles. Autophagy is not essential for oogenesis or fertilization. Oocytes lacking Atg5, which like Atg7, are involved in autophagosome formation, were fertilized normally in vivo [17]. Although autophagy activation was observed in fertilized oocytes at the two-cell stage, it was not observed in unfertilized oocytes [17]. Autophagy-deficient embryos, derived from Atg5-null oocytes, do not develop beyond the four- and eight-cell stages when fertilized with Atg5-null sperm, but develop normally if fertilized with an Atg5-plus sperm. Transient autophagy activation, which negatively regulates endoplasmic reticulum (ER) stress, increased the blastocyst development rate, trophectoderm cell number, and blastomere survival in bovine embryos [18]. Thus, autophagy seems to aid the development of zygotes (fertilized embryos), by refining excessive maternal factors during early embryonal development in mammals. In most eukaryotic species, the autophagy receptors p62 and gamma-aminobutyric acid receptor-associated protein (GABARAP) eliminate the mitochondria of sperm through mitophagy after fertilization [19]. The sperm mitochondrial proteins are degraded by the ubiquitin-proteasome system, but selective autophagy is partially used in this process. Autophagy activation in blastocysts, which is mediated by 17β-estradiol (E2), may contribute to delayed implantation, because E2-mediated autophagy activation allows dormant blastocysts to survive longer than those not treated with E2 [20]. In addition, progesterone, like E2, activates autophagy via suppression of mTOR in bovine mammary epithelial cells [21].
