Reduced signaling through the hedgehog pathway in the uterine stroma causes deferred implantation and embryonic loss

Abstract

The role of the hedgehog (HH) signaling pathway in implantation was studied in mice in which the HH signal transducer, smoothened (SMO), was conditionally deleted in the stromal compartment of the uterus, using CRE recombinase expressed through the Amhr2 -mutant mice, Smo mRNA in uterine stroma was reduced 49% compared to that in Amhr2control mice, while levels in the luminal epithelium were not different. Litter size was reduced 60% in mutants compared with controls, but ovulation rate and the number of implantation sites on day 7 of pregnancy did not differ. The number of corpora lutea was equivalent to the number of implantation sites, indicating that most ovulations resulted in implanted embryos. However, on days 13 to 15, the rate of embryo resorption was elevated in mutants. In control mice, on day 5, implantation sites were present and blastocysts were well-attached. In contrast, blastocysts were readily flushed from uteri of mutant mice on day 5 and implantation sites were rare. On days 5.5 and 6, implantation sites were present in mutant mice, and by day 6 embryos could not be flushed from the uterus. The weight of implantation sites on day 7 was decreased by 42% in mutant mice, consistent with delayed development. Signaling through SMO in the endometrial stroma is required for optimal timing of implantation, and deferred implantation leads to defective embryo development and subsequent pregnancy loss.

Changes in Mouse Uterine Transcriptome in Estrus and Proestrus1

“…This up regulation is indicative of the uterus being in a proliferative state in estrus. Ihh expression in the lumenal and glandular epithelium of the uterus increases in response to progesterone receptor signaling [73] and studies using transgenic mice showed that hedgehog signaling is essential for implantation [74]. The role of hedgehog signaling in the regulation of the reproductive cycle and the mechanisms of its interplay with other developmental pathways are only partially understood.…”

Characterization of the Endometrial Transcriptome in Early Diestrus Influencing Pregnancy Establishment in Dairy Cattle after Transfer of In-Vitro Produced Embryos

“…In addition, secondary pathways and upstream regulators previously associated with endometrial receptivity were identified, such as: (i) The Hedgehog pathway (Fig. 2i), constituted by genes upregulated in PR cows, involved in implantation and early embryo development 49,50 . (ii) The ribosome KEGG pathways (Fig.…”

Dysfunction of Shh signaling impaired trophoblast motility and autophagy is involved in poor placentation of recurrent miscarriage

“…Recently, the other study indicated that both previous miscarriages and single nucleotide polymorphisms (SNPs) rs3738880 in Gli2 were associated with anorectal malformations, though the relationship between miscarriages and SNP rs3738880 in Gli2 remains unknown [54]. Besides, conditionally deleted of Smo in the mouse uterus impairs implantation and subsequent pregnancy loss [55].…”