Cadence of procreation: orchestrating embryo-uterine interactions

Abstract

Embryo implantation in eutherian mammals is a highly complex process and requires reciprocal communication between different cell types of the embryo at the blastocyst stage and receptive uterus. The events of implantation are dynamic and highly orchestrated over a species-specific period of time with distinctive and overlapping expression of many genes. Delayed implantation in different species has helped elucidate some of the intricacies of implantation timing and different modes of the implantation process. How these events are coordinated in time and space are not clearly understood. We discuss potential regulators of the precise timing of these events with respect to central and local clock mechanisms. This review focuses on the timing and synchronization of early pregnancy events in mouse and consequences of their aberrations at later stages of pregnancy.

Keywords: Embryo implantation; Embryonic diapause; MSX; Temporal; Uterus.

Figure 1. A schematic diagram depicting the distinctive and overlapping expression of various transcription factors, morphogens, cytokines and signaling molecules around the time of implantation in the mouse uterus

Key signaling pathways for uterine receptivity, implantation, and decidualization in the context of cell types and temporal expression. BMP2, bone morphogenetic protein 2; cPLA2α, cytosolic phospholipase A2α; COUP-TFII, chicken ovalbumin upstream promoter transcription factor-2; Cox1, cyclooxygenase-1; Cox2, cyclooxygenase-2; gp130, glycoprotein 130; Hand2, heart- and neural crest derivatives-expressed protein 2; HB-EGF, heparin-binding epidermal growth factor-like growth factor; Hoxa10/11, homeobox A10/11; IHH, Indian hedgehog; KLF5, Kruppel-like factor 5; LIF, leukemia inhibitory factor; LPA3, lysophosphatidic acid receptor 3; MSX1, Muscle segment homeobox 1; PPAR-δ; peroxisome proliferators–activating receptor δ; RXR, retinoid X receptor; SGK1, serum- and glucocorticoid-inducible kinase 1; STAT3, signal transducer and activator of transcription 3; Wnt4/5a, Wingless-Type MMTV integration site family members 4/5a. LE, luminal epithelium (blue); GE, glandular epithelium (yellow); LE + GE (green); S, stroma (pink); LE + stroma (purple).

Figure 2. A potential scheme showing threshold of estrogen levels for the window of receptivity in the P₄-primed uterus

While estrogen at low levels below a threshold extends the window of uterine receptivity for implantation, levels above the threshold rapidly close this window, leading the uterus into a refractory state (Adapted from [43]).

Figure 3. Schematic of regulation of diapause by MSX in mouse, mink and tammar wallaby

Despite variation in the proximate stimuli and endocrine milieu to induce diapause in these species, the diverse pathways perhaps converge to work through MSX in the uterus, which regulates dormancy of blastocyst in diapause. Notably, blastocysts with an inner cell mass each are present in eutherian mammals but not in marsupials. Genetic and molecular studies in mice have shown inability of uteri to undergo true delay in the absence of uterine Msx genes and maintain blastocyst viability, potentially via upregulation of Wnt5a. Prolactin (PRL), progesterone (P₄) and estradiol-17β (E₂). Larger font size indicates higher levels of hormones (Adapted from [48]).