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Rac1 Regulates Endometrial Secretory Function to Control Placental Development.

Davila J, Laws MJ, Kannan A, Li Q, Taylor RN, Bagchi MK, Bagchi IC - PLoS Genet. (2015)

Bottom Line: Ablation of Rac1 did not affect the formation of the decidua but led to fetal loss in mid gestation accompanied by extensive hemorrhage.Consequently, the Rac1- 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- 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.

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- 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- 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.

No MeSH data available.


Related in: MedlinePlus

Enhanced trophoblast proliferation in Rac1 conditional-knockout mouse.(A) Expanded trophoblast cells in Rac1d/d uteri on day 8 of gestation. a: Hematoxylin and Eosin (H & E) staining of uterine sections from Rac1f/f and Rac1d/d mice on day 8 of pregnancy. Three representative images of Rac1d/d uterine sections are shown. b: Quantitation of embryonic areas in H & E stained uterine sections of Rac1f/f and Rac1d/d mice on day 8 of pregnancy. Data represent mean ± SEM from six separate samples and were analyzed by non-parametric t-test. Asterisks indicate statistically significant differences (*P < 0.05). (B) Increased proliferation of trophoblast cells in the ectoplacental cone (EPC) of Rac1d/d uteri. Uterine sections from Rac1f/f and Rac1d/d mice on days 7 (panels a and b) and 8 of pregnancy (panels c and d) were subjected to IF using PCNA and cytokeratin 8 (KRT8) antibodies. AMD, MD, and E denote antimesometrial decidua, mesometrial decidua, and embryo respectively.
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pgen.1005458.g005: Enhanced trophoblast proliferation in Rac1 conditional-knockout mouse.(A) Expanded trophoblast cells in Rac1d/d uteri on day 8 of gestation. a: Hematoxylin and Eosin (H & E) staining of uterine sections from Rac1f/f and Rac1d/d mice on day 8 of pregnancy. Three representative images of Rac1d/d uterine sections are shown. b: Quantitation of embryonic areas in H & E stained uterine sections of Rac1f/f and Rac1d/d mice on day 8 of pregnancy. Data represent mean ± SEM from six separate samples and were analyzed by non-parametric t-test. Asterisks indicate statistically significant differences (*P < 0.05). (B) Increased proliferation of trophoblast cells in the ectoplacental cone (EPC) of Rac1d/d uteri. Uterine sections from Rac1f/f and Rac1d/d mice on days 7 (panels a and b) and 8 of pregnancy (panels c and d) were subjected to IF using PCNA and cytokeratin 8 (KRT8) antibodies. AMD, MD, and E denote antimesometrial decidua, mesometrial decidua, and embryo respectively.

Mentions: Rac1- uteri exhibited embryo resorption on day 10 of pregnancy, but a closer histological examination of uterine sections revealed that embryos implanted in these uteri begin to show abnormalities as early as days 7–8 of gestation. Specifically, when we measured embryonic areas, we observed a significant expansion of the trophoblast cell layer in the embryos implanted in Rac1d/d uteri compared to those in Rac1f/f controls (Fig 5A). Further analyses of uterine sections on days 7 and 8 of pregnancy, using antibodies against PCNA, a cell proliferation marker, confirmed enhanced proliferation of the trophoblast cells, marked by cytokeratin 8 staining, within the ectoplacental cone (EPC) of Rac1d/d uteri (Fig 5B). We noted with interest that the timeframe of development of this embryonic phenotype in Rac1- uteri closely overlaps with that of induction of Rac1 expression in the endometrial stromal cells during decidualization.


Rac1 Regulates Endometrial Secretory Function to Control Placental Development.

Davila J, Laws MJ, Kannan A, Li Q, Taylor RN, Bagchi MK, Bagchi IC - PLoS Genet. (2015)

Enhanced trophoblast proliferation in Rac1 conditional-knockout mouse.(A) Expanded trophoblast cells in Rac1d/d uteri on day 8 of gestation. a: Hematoxylin and Eosin (H & E) staining of uterine sections from Rac1f/f and Rac1d/d mice on day 8 of pregnancy. Three representative images of Rac1d/d uterine sections are shown. b: Quantitation of embryonic areas in H & E stained uterine sections of Rac1f/f and Rac1d/d mice on day 8 of pregnancy. Data represent mean ± SEM from six separate samples and were analyzed by non-parametric t-test. Asterisks indicate statistically significant differences (*P < 0.05). (B) Increased proliferation of trophoblast cells in the ectoplacental cone (EPC) of Rac1d/d uteri. Uterine sections from Rac1f/f and Rac1d/d mice on days 7 (panels a and b) and 8 of pregnancy (panels c and d) were subjected to IF using PCNA and cytokeratin 8 (KRT8) antibodies. AMD, MD, and E denote antimesometrial decidua, mesometrial decidua, and embryo respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549291&req=5

pgen.1005458.g005: Enhanced trophoblast proliferation in Rac1 conditional-knockout mouse.(A) Expanded trophoblast cells in Rac1d/d uteri on day 8 of gestation. a: Hematoxylin and Eosin (H & E) staining of uterine sections from Rac1f/f and Rac1d/d mice on day 8 of pregnancy. Three representative images of Rac1d/d uterine sections are shown. b: Quantitation of embryonic areas in H & E stained uterine sections of Rac1f/f and Rac1d/d mice on day 8 of pregnancy. Data represent mean ± SEM from six separate samples and were analyzed by non-parametric t-test. Asterisks indicate statistically significant differences (*P < 0.05). (B) Increased proliferation of trophoblast cells in the ectoplacental cone (EPC) of Rac1d/d uteri. Uterine sections from Rac1f/f and Rac1d/d mice on days 7 (panels a and b) and 8 of pregnancy (panels c and d) were subjected to IF using PCNA and cytokeratin 8 (KRT8) antibodies. AMD, MD, and E denote antimesometrial decidua, mesometrial decidua, and embryo respectively.
Mentions: Rac1- uteri exhibited embryo resorption on day 10 of pregnancy, but a closer histological examination of uterine sections revealed that embryos implanted in these uteri begin to show abnormalities as early as days 7–8 of gestation. Specifically, when we measured embryonic areas, we observed a significant expansion of the trophoblast cell layer in the embryos implanted in Rac1d/d uteri compared to those in Rac1f/f controls (Fig 5A). Further analyses of uterine sections on days 7 and 8 of pregnancy, using antibodies against PCNA, a cell proliferation marker, confirmed enhanced proliferation of the trophoblast cells, marked by cytokeratin 8 staining, within the ectoplacental cone (EPC) of Rac1d/d uteri (Fig 5B). We noted with interest that the timeframe of development of this embryonic phenotype in Rac1- uteri closely overlaps with that of induction of Rac1 expression in the endometrial stromal cells during decidualization.

Bottom Line: Ablation of Rac1 did not affect the formation of the decidua but led to fetal loss in mid gestation accompanied by extensive hemorrhage.Consequently, the Rac1- 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- 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.

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- 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- 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.

No MeSH data available.


Related in: MedlinePlus