Bmp2 is critical for the murine uterine decidual response - PubMed (original) (raw)

Bmp2 is critical for the murine uterine decidual response

Kevin Y Lee et al. Mol Cell Biol. 2007 Aug.

Abstract

The process of implantation, necessary for all viviparous birth, consists of tightly regulated events, including apposition of the blastocyst, attachment to the uterine lumen, and differentiation of the uterine stroma. In rodents and primates the uterine stroma undergoes a process called decidualization. Decidualization, the process by which the uterine endometrial stroma proliferates and differentiates into large epithelioid decidual cells, is critical to the establishment of fetal-maternal communication and the progression of implantation. The role of bone morphogenetic protein 2 (Bmp2) in regulating the transformation of the uterine stroma during embryo implantation in the mouse was investigated by the conditional ablation of Bmp2 in the uterus using the (PR-cre) mouse. Bmp2 gene ablation was confirmed by real-time PCR analysis in the PR-cre; Bmp2fl/fl (termed Bmp2d/d) uterus. While littermate controls average 0.9 litter of 6.2+/-0.7 pups per month, Bmp2d/d females are completely infertile. Analysis of the infertility indicates that whereas embryo attachment is normal in the Bmp2d/d as in control mice, the uterine stroma is incapable of undergoing the decidual reaction to support further embryonic development. Recombinant human BMP2 can partially rescue the decidual response, suggesting that the observed phenotypes are not due to a developmental consequence of Bmp2 ablation. Microarray analysis demonstrates that ablation of Bmp2 leads to specific gene changes, including disruption of the Wnt signaling pathway, Progesterone receptor (PR) signaling, and the induction of prostaglandin synthase 2 (Ptgs2). Taken together, these data demonstrate that Bmp2 is a critical regulator of gene expression and function in the murine uterus.

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Figures

FIG. 1.

FIG. 1.

Decidualization in Bmp2 f/f and Bmp2 d/d mice. (a) Gross morphology of the decidual response in Bmp2 f/f and Bmp2 d/d uteri 5 days after the decidual stimulus. (b) Ratio of the decidual horn to the control horn weight of Bmp2 f/f and Bmp2 d/d uteri 5 days after the decidual stimulus. *, P = 3.8 e-4 from Bmp2 f/f mice. (c) Differentiation as measured by alkaline phosphatase staining in the Bmp2 f/f and_Bmp2_ d/d uterus 48 h after the decidual trauma. (d) Differentiation as measured by alkaline phosphatase staining in the Bmp2 d/d uterus treated with 10% BSA or 167 ng of human recombinant Bmp2/μl in 10% BSA 48 h after the decidual trauma. Original magnification, ×10.

FIG. 2.

FIG. 2.

Bmp2 ablation affects differentiation and proliferation but not vascularization. (a) Proliferation as measured by immunohistochemical staining of phosphorylated histone H3 in Bmp2 f/f and Bmp2 d/d uteri prior to and 24 and 48 h after the decidual trauma. Slides are counterstained with nuclear fast red. (b) Quantification of phosphorylated histone H3-positive cells. The data are shown as means ± the standard error of the mean (SEM). Sections from three uteri of each genotype were counted at all time points. *, P = 8.36 e-5 from Bmp2 f/f at 48 h. (c) Vascularization as measured by CD31 immunofluorescence in Bmp2 f/f and Bmp2 d/d uteri prior to and 24 and 48 h after the decidual trauma. Slides are counterstained with DAPI. (d) Differentiation as measured by alkaline phosphatase staining in Bmp2 f/f and Bmp2 d/d uteri 24 and 48 h after the decidual trauma. Slides are counterstained with nuclear fast red. Original magnification, ×20.

FIG. 3.

FIG. 3.

Bmp2 ablation deregulates Wnt signaling. Real-time PCR in Wnt4 (a), Wnt6 (b), Sfrp4 (c), and Dact1 in Bmp2 f/f and Bmp2 d/d uteri. The data shown as means ± the SEM. *, P < 0.01 from Bmp2 f/f at the corresponding time point; **, P < 0.05 from Bmp2 f/f at the corresponding time point.

FIG. 4.

FIG. 4.

Bmp2 ablation deregulates the expression and action of FK-506-binding proteins. Real-time PCR in Fkbp3 (a), Fkbp4 (b), Fkbp5 (c), and Frap1 (d) in Bmp2 f/f and Bmp2 d/d uteri. The data shown as means ± the SEM. *, P < 0.01 from Bmp2 f/f at the corresponding time point; **, P < 0.05 from Bmp2 f/f at the corresponding time point. (e) PR immunohistochemistry in Bmp2 f/f and Bmp2 d/d uteri 24 h after the decidual trauma. (f) Western blot for phosphorylated and total PR 24 h after the decidual trauma. (g) Expression of Frap1 by immunofluorescence. The arrow indicates retained epithelial expression. Original magnification, ×20. High-power insets are at ×40 magnification.

FIG. 5.

FIG. 5.

Bmp2 acts upstream of Ptgs2. (a) Real-time PCR in Ptgs2 in Bmp2 f/f and Bmp2 d/d uteri. Real-time PCR of Bmp2 (b), Wnt4 (c), Fkbp4 (d), Fkbp5 (e), and Frap1 (f), in _Ptgs2_−/− and littermate control uteri. The data shown as means ± the SEM. *, P < 0.01 from Bmp2 f/f at the corresponding time point; *, P < 0.05 from Bmp2 f/f at the corresponding time point.

FIG. 6.

FIG. 6.

Model depicting the relationships of genes during implantation.

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