Mouse Sox17 haploinsufficiency leads to female subfertility due to impaired implantation

Abstract

Embryonic implantation comprises a dynamic and complicated series of events, which takes place only when the maternal uterine endometrium is in a receptive state. Blastocysts reaching the uterus communicate with the uterine endometrium to implant within a narrow time window. Interplay among various signalling molecules and transcription factors under the control of ovarian hormones is necessary for successful establishment of pregnancy. However, the molecular mechanisms that allow embryonic implantation in the receptive endometrium are still largely unknown. Here, we show that Sry-related HMG box gene-17 (Sox17) heterozygous mutant female mice exhibit subfertility due to implantation failure. Sox17 was expressed in the oviduct, uterine luminal epithelium, and blood vessels. Sox17 heterozygosity caused no appreciable defects in ovulation, fertilisation, blastocyst formation, and gross morphology of the oviduct and uterus. Another group F Sox transcription factor, Sox7, was also expressed in the uterine luminal and glandular epithelium relatively weakly. Despite uterine Sox7 expression, a significant reduction in the number of implantation sites was observed in Sox17 heterozygous mutant females due to haploinsufficiency. Our findings revealed a novel role of Sox17 in uterine receptivity to embryo implantation.

A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function

“…Similarly, motifs of Sex Determining Region Y Box (SOX) factors are also enriched in the uterine, but not the HPC7 cell GATA2 cistrome (Table S4). It is worthy to note that, SOX17 is also expressed in the uterine epithelial cells (Rubel et al, 2012b), where GATA2 is expressed, and functions in the process of embryo implantation (Hirate et al, 2016). These findings revealed a uterine-specific GATA2 occupancy pattern that is associated with the presence of binding motifs of transcription factors, such as PGR, and SOX17 that have been known to regulate uterine function.…”

“…6B) that consists of GATA2, PGR and SOX17 transcription factors (Guimaraes-Young et al, 2016; Hirate et al, 2016; Rubel et al, 2012a; Rubel et al, 2012b). To investigate this network in human endometrial samples, we performed path analyses on the GSE58144 dataset using a structural equation modeling (Xiong et al, 2004).…”

“…In this group, the binding motif for Forkhead box (FOX) proteins is enriched in the GATA2 occupying sites, which bears a resemblance of co-occupancy of GATA2 and FOXA1 in genomic loci of AR target genes in prostate cancer (Wu et al, 2014). Furthermore, the enrichment of SOX (Sex Determining Region Y Box) factor binding motifs also implicates a potential interaction between GATA2 and other uterine transcription regulators such as SOX17 (Garcia et al, 2007; Guimaraes-Young et al, 2016; Hirate et al, 2016). These results indicate future investigations on potential mechanisms by which GATA2 and PGR work independently with other transcription regulators to direct gene expression in the uterus.…”

Three-Dimensional High-Frequency Ultrasonography for Early Detection and Characterization of Embryo Implantation Site Development in the Mouse

“…Notably, many mouse models of implantation or early pregnancy failure require study in the immediate post-implantation time frame, beginning at 5.5 d.p.c. [7, 21–23]. In studies described here, the ability to accurately detect implantation site number, location, and growth from 5.5 d.p.c onwards in both 2-D and 3-D visual reconstruction in the pregnant mouse provides clear advantages over earlier studies that were limited to mid-pregnancy and used only 2-D imaging [14, 15].…”

Hormone dependent uterine epithelial-stromal communication for pregnancy support

“…Recently, new gene editing technology, such as CRISPR/Cas9 system has opened a new era for the generation of transgenic animal models in a more efficient and economical way that can help further identify uterine-specific enhancer or promoter regions of these PGR-associated genes. For example, PGR and GATA2 both occupy at putative enhancers of the Sox17 and Ihh genes [45] that have pivotal uterine functions [54, 91, 92]. While results from in vitro assays suggest a cooperation of PGR and GATA2 in the regulation of enhancers for the Sox17 and Ihh genes, the in vivo function of such enhancers remains to be demonstrated, perhaps by CRISPR technology.…”