Blastocyst implantation in mice occurs on the evening of day 4 of pregnancy and requires progesterone and estrogen secreted from the ovary. The preimplantation estrogen secretion which occurs in the midmorning of day 4 is an absolute requirement for the activation of blastocysts for implantation; its removal by ovariectomy delays implantation, with blastocysts surviving in the uterus unimplanted in a "dormant" state. In experimentally delayed implantation in mice, dormant blastocysts have been shown to survive more than 3 weeks in the absence of both estrogen and progesterone. Dormant blastocysts cannot initiate implantation, and many molecules required for attachment to the uterine lining are downregulated. Delayed implantation also occurs in lactating rodents. Prolonged gestation in suckling rodents is due to a "physiological delay" of implantation. The removal of the suckling litter or an injection of estrogen can reactivate the implantation process. In many mammals, including marsupials and mustelids, obligate diapause occurs during the preimplantation period of every pregnancy.
Autophagy is a major cellular catabolic pathway and is the only process known to degrade intact organelles. It is the primary intracellular mechanism for degrading and recycling long-lived proteins and organelles. Suboptimal extracellular environments (nutrient starvation, hypoxia, overcrowding) and intracellular stress (accumulation of damaged cytoplasmic components) induce autophagy. For example, in the life cycle of nematodes, crowding or a shortage of food causes L1 or L2 worms to form dauers with low metabolisms and extended longevity. Formation of dauers has been shown to involve autophagic activation in certain cells.
Dormant blastocysts are metabolically quiescent and exhibit extended longevity in utero without initiating implantation. In some aspects, therefore, dormant blastocysts resemble the dauers of nematodes. But the underlying mechanism that results in the extended life-span of dormant blastocysts in utero remains elusive. Our recent work showed that autophagy is activated for the survival and extended longevity of dormant blastocysts during delayed implantation. Furthermore, prolonged activation of autophagy is associated with the compromised developmental competence of embryos.
Our lab is currently working on identifying the regulation of autophagy in embryonic systems. This work will provide novel information on the role for autophagy in mammalian developmental processes and in the long run, will provide solutions to help find factors associated with embryonic demise around the time of implantation, a leading cause of infertility in women.