Pre-implantation conceptus-maternal communication in the horse: What can we learn from asynchronous embryo transfer?

The pre-implantation period is a critical time for the establishment and maintenance of pregnancy and, in the mare as in other species, is characterized by a high incidence of embryonic loss. The equine conceptus develops for an usually long period within the uterine cavity (40-42 days) before implantation begins and a stable attachment is formed. Moreover, at the time of implantation, the equine embryo has already undergone a number of critical developmental events such as gastrulation, neurulation and initial organogenesis to reach the fetal stage. During its prolonged pre-implantation period, the equine conceptus is entirely dependent on the uterine luminal environment and, in particular, on the uterine secretions or ‘histotroph’ for nutrient provision. Since the luminal epithelium and endometrial glands synthesize, transport and/or secrete the histotroph into the uterine lumen, it is important to understand the mechanisms involved in regulating endometrial secretion of the molecules required for conceptus survival and development.
The main focus of this thesis was to improve our understanding of the role of the uterine environment in supporting conceptus development and, in particular, to dissect the importance of maternal progesterone and conceptus-secreted factors in preparing the uterus for its role during pre-implantation development in the horse. To better understand the impact of the uterine environment on conceptus development, and to differentiate between the effects of progesterone and/or the embryo on endometrial gene expression we employed an equine asynchronous embryo transfer model.
In this thesis, we show that the horse conceptus is sensitive to the uterine environment to which it is exposed and, in the case of uterine asynchrony, is able to adapt its development accordingly, in order to ensure subsequent roughly synchronous development. Reflecting this adaptability, we found that the endometrial transcriptome is subtly different in a uterus in the presence of a more advanced embryo (i.e. very few DEGs). By contrast, the conceptus is markedly affected (retarded) by a less advanced uterus; this is mainly a result of a shorter duration of endometrial exposure to progesterone, but presumably compounded by the influence of the conceptus itself as it succumbs to developmental retardation. The different gene expression profile of a uterus exposed to a shorter period of progesterone priming will result in a different histotrophic composition, which is presumably the primary signal/factor resulting in developmental retardation of the conceptus. Interestingly, the equine conceptus appears to have an unusual ability to not only sense the changes in the uterine environment but also to delay its development and wait for the endometrium to catch-up, thereby allowing the conceptus to survive. In this respect, it is possible that specific pathways (for example the kinin-kallikrein system) assist or enable the conceptus to detect the stage of the endometrium and regulate its development accordingly. Finally, nutrient transporters and the IGF system, which are required for placental nutrient uptake or development, respectively, are expressed from early on in pregnancy and their expression adapts over time, presumably to optimally support the needs of the equine conceptus during its unusually long pre-implantation period.