Foxa2-dependent uterine glandular cell differentiation is essential for successful implantation

Uterine receptivity is essential for successful implantation. 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 on day 4 of pregnancy. Interestingly, Foxa2-deficient glands lacking LIF production fail to develop branches and the functional Prss29+ subgroup. This Prss29+ subgroup develops prior to estrogen secretion. 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. The "transitional phase", predicting uterine receptivity one day before implantation, is a landmark concept in uterine receptivity. Determining uterine receptivity before embryo transfers is a major barrier in IVF. Here they identify a FOXA2-dependent preimplantation differentiation process in uterine glands that yields expanded branching, and which could be a useful measure of uterine receptivity.