Limits...
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

Abnormal trophoblast proliferation, differentiation and disorganized placentation in Rac1 conditional-knockout mouse.(A & B) Increased population of trophoblast giant cells (TGCs) in the placenta of Rac1d/d uteri. (A) H and E staining of uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy. TGC and MD indicate trophoblast giant cells and mesometrial decidua, respectively. TGCs are demarcated by dashed lines. Arrows indicate chorionic plate and arrow-heads indicate TGCs. (B) Uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy were subjected to IF using PL1. (C) Uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy were subjected to IF using TPBPA and KRT8 antibodies. (D) H and E staining of uterine sections from Rac1f/f and Rac1d/d mice on day 12 of pregnancy. TGC, MD and E indicate trophoblast giant cells, mesometrial decidua, and embryo, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4549291&req=5

pgen.1005458.g006: Abnormal trophoblast proliferation, differentiation and disorganized placentation in Rac1 conditional-knockout mouse.(A & B) Increased population of trophoblast giant cells (TGCs) in the placenta of Rac1d/d uteri. (A) H and E staining of uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy. TGC and MD indicate trophoblast giant cells and mesometrial decidua, respectively. TGCs are demarcated by dashed lines. Arrows indicate chorionic plate and arrow-heads indicate TGCs. (B) Uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy were subjected to IF using PL1. (C) Uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy were subjected to IF using TPBPA and KRT8 antibodies. (D) H and E staining of uterine sections from Rac1f/f and Rac1d/d mice on day 12 of pregnancy. TGC, MD and E indicate trophoblast giant cells, mesometrial decidua, and embryo, respectively.

Mentions: To assess the impact of dysregulated proliferation of trophoblast cells in the EPC on placenta formation, we performed histological analyses of uterine sections of Rac1d/d and Rac1d/d mice on day 10 of gestation. As expected, the placentae of Rac1f/f mice displayed normal characteristics of one to two layers of trophoblast giant cells (TGC) at the maternal-fetal interface on day 10. In contrast, we observed up to four or five layers of TGCs in Rac1d/d animals (Fig 6A). The abnormal expansion of the TGCs in the placentae of Rac1d/d mice was further confirmed when we subjected uterine sections to immunofluorescence analyses using antibodies against PL1, a TGC-specific marker [33–35]. Consistent with the results shown in Fig 6A, multiple layers of TGCs were evident at the maternal-fetal interface in Rac1d/d mice compared to one or two layers in Rac1f/f mice (Fig 6B). The spatial distribution of the spongiotrophoblast cells, a subtype of TGCs, as indicated by the expression of their biomarker TPBPA [33–35], was identical in the placentae of Rac1f/f and Rac1d/d mice (Fig 6C). As pregnancy progressed to day 12, the Rac1d/d placentae appeared to be highly disorganized, lacking properly formed layers, including the labyrinth (Fig 6D). Taken together, our results indicated that decidual expression of Rac1 critically controls the proliferation and differentiation of the TGCs at the maternal-fetal interface and ensures proper placenta development and structure.


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)

Abnormal trophoblast proliferation, differentiation and disorganized placentation in Rac1 conditional-knockout mouse.(A & B) Increased population of trophoblast giant cells (TGCs) in the placenta of Rac1d/d uteri. (A) H and E staining of uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy. TGC and MD indicate trophoblast giant cells and mesometrial decidua, respectively. TGCs are demarcated by dashed lines. Arrows indicate chorionic plate and arrow-heads indicate TGCs. (B) Uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy were subjected to IF using PL1. (C) Uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy were subjected to IF using TPBPA and KRT8 antibodies. (D) H and E staining of uterine sections from Rac1f/f and Rac1d/d mice on day 12 of pregnancy. TGC, MD and E indicate trophoblast giant cells, mesometrial decidua, and embryo, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005458.g006: Abnormal trophoblast proliferation, differentiation and disorganized placentation in Rac1 conditional-knockout mouse.(A & B) Increased population of trophoblast giant cells (TGCs) in the placenta of Rac1d/d uteri. (A) H and E staining of uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy. TGC and MD indicate trophoblast giant cells and mesometrial decidua, respectively. TGCs are demarcated by dashed lines. Arrows indicate chorionic plate and arrow-heads indicate TGCs. (B) Uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy were subjected to IF using PL1. (C) Uterine sections from Rac1f/f and Rac1d/d mice on day 10 of pregnancy were subjected to IF using TPBPA and KRT8 antibodies. (D) H and E staining of uterine sections from Rac1f/f and Rac1d/d mice on day 12 of pregnancy. TGC, MD and E indicate trophoblast giant cells, mesometrial decidua, and embryo, respectively.
Mentions: To assess the impact of dysregulated proliferation of trophoblast cells in the EPC on placenta formation, we performed histological analyses of uterine sections of Rac1d/d and Rac1d/d mice on day 10 of gestation. As expected, the placentae of Rac1f/f mice displayed normal characteristics of one to two layers of trophoblast giant cells (TGC) at the maternal-fetal interface on day 10. In contrast, we observed up to four or five layers of TGCs in Rac1d/d animals (Fig 6A). The abnormal expansion of the TGCs in the placentae of Rac1d/d mice was further confirmed when we subjected uterine sections to immunofluorescence analyses using antibodies against PL1, a TGC-specific marker [33–35]. Consistent with the results shown in Fig 6A, multiple layers of TGCs were evident at the maternal-fetal interface in Rac1d/d mice compared to one or two layers in Rac1f/f mice (Fig 6B). The spatial distribution of the spongiotrophoblast cells, a subtype of TGCs, as indicated by the expression of their biomarker TPBPA [33–35], was identical in the placentae of Rac1f/f and Rac1d/d mice (Fig 6C). As pregnancy progressed to day 12, the Rac1d/d placentae appeared to be highly disorganized, lacking properly formed layers, including the labyrinth (Fig 6D). Taken together, our results indicated that decidual expression of Rac1 critically controls the proliferation and differentiation of the TGCs at the maternal-fetal interface and ensures proper placenta development and structure.

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