Global gene expression analysis identifies molecular pathways distinguishing blastocyst dormancy and activation

Abstract

Delayed implantation (embryonic diapause) occurs when the embryo at the blastocyst stage achieves a state of suspended animation. During this period, blastocyst growth is very slow, with minimal or no cell division. Nearly 100 mammals in seven different orders undergo delayed implantation, but the underlying molecular mechanisms that direct this process remain largely unknown. In mice, ovariectomy before preimplantation ovarian estrogen secretion on day 4 of pregnancy initiates blastocyst dormancy, which normally lasts for 1-2 weeks by continued progesterone treatment, although blastocyst survival decreases with time. An estrogen injection rapidly activates blastocysts and initiates their implantation in the progesterone-primed uterus. Using this model, here we show that among Ϸ20,000 genes examined, only 229 are differentially expressed between dormant and activated blastocysts. The major functional categories of altered genes include the cell cycle, cell signaling, and energy metabolic pathways, particularly highlighting the importance of heparin-binding epidermal growth factor-like signaling in blastocyst-uterine crosstalk in implantation. The results provide evidence that the two different physiological states of the blastocyst, dormancy and activation, are molecularly distinguishable in a global perspective and underscore the importance of specific molecular pathways in these processes. This study has identified candidate genes that provide a scope for in-depth analysis of their functions and an opportunity for examining their relevance to blastocyst dormancy and activation in numerous other species for which microarray analysis is not available or possible due to very limited availability of blastocysts.S uccessful implantation results from reciprocal interactions between an implantation-competent blastocyst and a receptive uterus. Highly coordinated cellular and molecular events, directed by ovarian estrogen and progesterone (P 4 ), produce a favorable uterine environment, the receptive state, to support implantation. The blastocyst also functions as an active unit with its own molecular program of cell growth and differentiation (1, 2). It is difficult to distinguish embryonic and uterine events during normal pregnancy with respect to blastocyst activation and uterine receptivity because of the changing levels of ovarian hormones. Because estrogen is essential for on-time uterine receptivity and blastocyst activation in mice (3), ovariectomy before preimplantation estrogen secretion on the morning of day 4 results in implantation failure, initiating a state of blastocyst dormancy. This condition, referred as delayed implantation, can be maintained by continued P 4 treatment. However, implantation with blastocyst activation rapidly occurs by an estrogen injection in P 4 -primed mice (3, 4). Delayed implantation also occurs naturally (facultative) during lactation after postpartum ovulation and successful mating in mice; implantation occurs after termination of the suckling stimulus (5). Lactational delay ...

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“…Implantation is the result of reciprocal interaction between the implantation-competent blastocyst and receptive uterus (Hamatani et al 2004). The uterus differentiates into an altered state when blastocysts are capable of mediating effective two-way communication to initiate the process of implantation .…”

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Molecular cues to the anti-implantation effect of nano-puerarin in rats

“…Implantation is the result of reciprocal interaction between the implantation-competent blastocyst and receptive uterus (Hamatani et al 2004). The endometrium differentiates into an altered state when the blastocysts are capable of mediating effective two-way communication to initiate the process of implantation (Dey et al 2004).…”