(160) Foxa2-Dependent Uterine Glandular Cell Differentiation Is Essential For Successful Implantation

Xiaofei Sun^1,2; Zhaoyu Jia³; Bo Li^1,2; Mitsunori Matsuo^1,2; Amanda Dewar^1,2; Anxhela Mustafaraj^1,2; Sudhansu K. Dey^1,2; Jia Yuan³

¹Reproductive Sciences Center, Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA

²College of Medicine, University of Cincinnati, Cincinnati, OH 45221, USA

³Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.

Abstract Text: Uterine receptivity (the window of implantation) is essential for successful implantation. The concept of uterine receptivity was first discovered over 50 years ago by Psychoyos. In mice, uterine receptivity begins with the secretion of LIF from uterine glands stimulated by estrogen on the morning of day 4 pregnancy. We hypothesize that gland readiness for estrogen stimulation is indispensable for uterine receptivity. The current study reveals that uterine glands undergo a differentiation process with expanded branching during the preimplantation period. The single cell RNA profiling of glandular cells identifies that LIF is expressed exclusively in a Prss29+ subgroup of glandular cells in response to estrogen secretion on day 4 of pregnancy. Previous studies have shown that Foxa2 deficiency in uterine glands results in implantation failure due to lack of LIF production. Interestingly, Foxa2-deficient glands fail to develop branches and the functional Prss29+ subgroup of gland cells, indicating FOXA2 is obligatory for normal glandular differentiation prior to implantation. We found that this group develops by the evening of day 3 of pregnancy prior to estrogen secretion on day 4 morning. We observed that Lif mRNA signals are present in the Prss29+ subgroup of glandular cells. Collectively, our findings show that uterine glands undergo a FOXA2-dependent maturation process to acquire the competence, named “transitional phase”, for entering the receptive phase. This newly identified "transitional phase", predicting uterine receptivity one day before implantation in mice, is a landmark concept in uterine receptivity and implantation biology.