Rac1 Regulates Endometrial Secretory Function to Control Placental Development

Abstract

During placenta development, a succession of complex molecular and cellular interactions between the maternal endometrium and the developing embryo ensures reproductive success. The precise mechanisms regulating this maternal-fetal crosstalk remain unknown. Our study revealed that the expression of Rac1, a member of the Rho family of GTPases, is markedly elevated in mouse decidua on days 7 and 8 of gestation. To investigate its function in the uterus, we created mice bearing a conditional deletion of the Rac1 gene in uterine stromal cells. Ablation of Rac1 did not affect the formation of the decidua but led to fetal loss in mid gestation accompanied by extensive hemorrhage. To gain insights into the molecular pathways affected by the loss of Rac1, we performed gene expression profiling which revealed that Rac1 signaling regulates the expression of Rab27b, another GTPase that plays a key role in targeting vesicular trafficking. Consequently, the Rac1-null decidual cells failed to secrete vascular endothelial growth factor A, which is a critical regulator of decidual angiogenesis, and insulin-like growth factor binding protein 4, which regulates the bioavailability of insulin-like growth factors that promote proliferation and differentiation of trophoblast cell lineages in the ectoplacental cone. The lack of secretion of these key factors by Rac1-null decidua gave rise to impaired angiogenesis and dysregulated proliferation of trophoblast cells, which in turn results in overexpansion of the trophoblast giant cell lineage and disorganized placenta development. Further experiments revealed that RAC1, the human ortholog of Rac1, regulates the secretory activity of human endometrial stromal cells during decidualization, supporting the concept that this signaling G protein plays a central and conserved role in controlling endometrial secretory function. This study provides unique insights into the molecular mechanisms regulating endometrial secretions that mediate stromal-endothelial and stromal-trophoblast crosstalk critical for placenta development and establishment of pregnancy.

Murine transcription factor Math6 is a regulator of placenta development

“…6 ). Interestingly and in contrast to this, the insulin-growth factor binding proteins IGFBP1 and IGFBP4, which are paracrine regulators of trophoblast proliferation 27 , were found to be up-regulated by a 3.6- and 2.6-fold change, respectively. Concerning uNK cells we found contradictory results.…”

“…In fact, IGFPB and prolactin-related proteins are inversely regulated, but both are important for the maternal-fetal communication by an endocrine process. Thus, controlled IGFBP secretion by decidual cells regulates trophoblast proliferation indirectly by buffering the bioavailability of insulin-like growth factor 27 . Furthermore, the importance of Prl3c1 and Prl8a2 for the overall endocrine function of the decidua was shown previously 42 , 43 .…”

MicroRNA-155 Controls Exosome Synthesis and Promotes Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma

“…For immunoblotting analysis, cellular and exosomal proteins were harvested with RIPA buffer 18 19 , and divided into aliquots that had a protein concentration of 1.0 μg/μl. Immunoblotting was performed using antibodies that detect CD63 (Santa Cruz), TP53INP1 (Santa Cruz), and ACTB (Sigma-Aldrich) 49 50 51 . Immunocytochemistry to detect RAB27B (Santa Cruz) and TP53INP1 was conducted on cells as described previously 52 .…”

Inside the Endometrial Cell Signaling Subway: Mind the Gap(s)

“…Whether EV-EMMPRIN can act on trophectoderm cells or on neighboring endometrial epithelial cells to contribute to invasion and migration has yet to be explored. In support of the role of EVs in the mechanisms regulating migration, endometrial stromal cell Rac-1 pathway seems to elevate vesicular trafficking [ 158 ]. Considering the recent meta-analysis pointing out that numerous genes contained within the human uterine fluid during the secretory phase are involved in vesicle trafficking, the concept of EV-mediated migration of endometrial cells during implantation deserves attention and is set to create a new research trajectory [ 132 ].…”