Bone Morphogenetic Protein 2 Functions via a Conserved Signaling Pathway Involving Wnt4 to Regulate Uterine Decidualization in the Mouse and the Human

A critical role of progesterone (P) during early pregnancy is to induce differentiation of the endometrial stromal cells into specialized decidual cells that support the development of the implanting embryo. The P-induced signaling pathways that participate in the formation and function of the decidual cells remain poorly understood. We report here that the expression of the bone morphogenetic protein 2 (BMP2), a morphogen belonging to the TGFβ superfamily, is induced downstream of P action in the mouse uterine stroma during decidualization. To determine the function of BMP2 during this differentiation process, a in stromal cells mouse decidualization. BMP2 to stromal the differentiation We that of BMP2 expression in cells the differentiation expression a downstream of BMP2 in stromal cells decidualization. of expression stromal differentiation in that is a of decidualization. We a in the expression of BMP2 in endometrial stromal cells during in in to and of BMP2 to to a of expression and the differentiation a BMP2 and that P-induced stromal in the mouse and the A critical role of progesterone (P) during early pregnancy is to induce differentiation of the endometrial stromal cells into specialized decidual cells that support the development of the implanting embryo. The P-induced signaling pathways that participate in the formation and function of the decidual cells remain poorly understood. We report here that the expression of the bone morphogenetic protein 2 (BMP2), a morphogen belonging to the TGFβ superfamily, is induced downstream of P action in the mouse uterine stroma during decidualization. To determine the function of BMP2 during this differentiation process, a in stromal cells mouse decidualization. BMP2 to stromal the differentiation We that of BMP2 expression in cells the differentiation expression a downstream of BMP2 in stromal cells decidualization. of expression stromal differentiation in that is a of decidualization. We a in the expression of BMP2 in endometrial stromal cells during in in to and of BMP2 to to a of expression and the differentiation a BMP2 and that P-induced stromal in the mouse and the The progesterone (P) progesterone bone morphogenetic protein progesterone bone morphogenetic protein and in to uterine of A role of P is to induce differentiation of the endometrial stromal cells into decidual cells of the this differentiation process, is a and is the of to the uterine of The is the and differentiation of the stromal cells the implanting to the decidual of the The decidual cells to and that critical that and function during pregnancy of of P-induced signaling that participate in the formation and function of this remain poorly is that the of the of P the progesterone in of role of in in the a mouse a of this of in the of a decidual and to support To is to the of that this during the differentiation To this a pathways to the and function We to the expression in the this the of that P of bone morphogenetic (BMP2), a of the TGFβ of We that BMP2 and in the uterine stroma in a decidual during early the that BMP2 is a of the stromal differentiation during decidualization. To the function of BMP2 in a in stromal cells mouse decidualization. this in that the BMP2 signaling a critical role in and a of and in of of expression in the the endometrial stromal cells a differentiation process, during the of the of a of protein and in stromal cells The of in stromal differentiation remain this that BMP2 is induced in endometrial stromal cells during that a BMP2 and downstream in the BMP2 and in the of the and of The the of and of and the endometrial and endometrial to the the of in and the of and the of early of the the and endometrial to BMP2 and and stromal and BMP2 and of and of in of to the uterine and into uterine in and and The and the to the endometrial The in and in the the endometrial stromal The of the a in and cells a cells in The cells and of P and to mouse BMP2 and and The in the uterine stromal cells the of of of to and into a of in the the function during the in uterine expression in to the of pregnancy and during the The uterine to mouse We expression in the decidual in to of the bone morphogenetic (BMP2), a morphogen that a of and the of the the of and a BMP2 A to BMP2 in the of pregnancy in the uterine that the BMP2 is a downstream of in the decidual the expression of BMP2 protein in mouse during early pregnancy BMP2 expression in uterine in the BMP2 in the stromal cells the in the uterine of of pregnancy the BMP2 in the stromal cells in the of the in the cells of the stroma pregnancy to BMP2 expression in the stromal cells the of the of and that and BMP2 signaling We the expression of in in in the stromal cells of and of the expression in the decidual and The in the to the that BMP2 and in the uterine stroma during of in the role of signaling in uterine a mouse in stromal cells in of uterine stromal and and of of pregnancy and The and the to the stromal The stromal cells a and in the of the and of the cells to of decidual cells a and We the in the expression of and decidual protein of uterine stromal differentiation the of stromal to a in the expression of and and The and in a of uterine stromal cells in the BMP2 expression in stromal expression of BMP2 protein of The BMP2 expression a stromal mouse in decidualization. cells mouse in the of P and cells and to 2 cells and a of in of stromal cells and The of to expression in the stromal cells to The of expression that of is cells and to the of BMP2 signaling during stromal BMP2 to stromal and the differentiation of BMP2 to and We that of BMP2 the of the of cells A that the of in a and BMP2 that this morphogen stromal differentiation We a in the expression of in stromal cells in to of The stromal cells of cells that BMP2 stromal stromal to the differentiation of stromal cells in the of and of BMP2 and a of and in of of in of stromal cells and the of and of The of the in a The in expression of in the stromal cells of BMP2 The of expression that of is of in stromal cells in the of the signaling the in in the signaling to in to the BMP2 is to pathways protein in of BMP2 the of that BMP2 signaling in stromal cells during of the role of BMP2 stromal of stromal cells of and to the BMP2 cells a We that the cells BMP2 in BMP2 expression cells in BMP2 expression cells that the cells BMP2 a in BMP2 this expression of BMP2 decidualization. stromal cells BMP2 the of of BMP2 stromal cells and BMP2 BMP2 protein of and stromal cells and BMP2 the of this of BMP2 expression during stromal in of BMP2 in the stromal cells to a in expression of differentiation and the of in cells BMP2 that BMP2 expression is critical of the stromal differentiation during a of BMP2 during the downstream of BMP2 signaling during expression of uterine stromal cells BMP2 We that the expression of of BMP2 and of the expression in to To the uterine stromal cells and the expression of and cells a of expression in to BMP2 during stromal differentiation in the expression of and in to A of expression in to BMP2 a in the of of of BMP2 to the stromal the of to that a downstream of BMP2 signaling in uterine stromal is induced in decidual stromal cells in to stromal cells BMP2 and to and of in to cells BMP2 and to and to mouse stromal cells BMP2 to the stromal of to and stromal cells the of of in of expression stromal in stromal cells to the of this the of of expression a in the expression of differentiation and that is a critical of stromal of BMP2 and in during the and of the expression of BMP2 in endometrial stromal cells during in decidualization. stromal cells endometrial in the of the in and to in to a and We the of and protein during this in the expression of BMP2 during in a of this in stromal cells in to the early of the The of BMP2 The expression of BMP2 protein a of expression that is during stromal and expression that of BMP2 that the expression of BMP2 and induced during stromal in the is in the stromal cells expression and differentiation of endometrial stromal of stromal cells endometrial of The cells in The cells a P and cells of and to and of BMP2 in stromal cells during in decidualization. and and of and of stromal cells the and BMP2 and to and and cells and P and and BMP2 and of in the role of BMP2 in stromal differentiation BMP2 to endometrial stromal cells that to in the of and of the to a of and during the in the of and of BMP2 the to the expression of that of of a of in to BMP2 during stromal differentiation that a critical of in the in the and a signaling downstream early P the of endometrial stromal cells into decidual a that is To the signaling pathways in the of the decidual of the expression to the expression is in mouse in to a this a signaling BMP2 and downstream of signaling to stromal The of this report is that this is during mouse and endometrial a of belonging to the TGFβ of to induce formation of and to a of and in a of during development in that to in mouse during the decidual of is in the cells of expression is in the stroma to the BMP2 is in the stromal cells the embryo. and in the decidual cells is the of in uterine and that of the in induced BMP2 that BMP2 expression is of that BMP2 is the of the expression is P in the expression of BMP2 and in the stromal cells during early pregnancy that this morphogen is a critical of decidualization. The of mouse stromal a role of BMP2 during the decidual We that of BMP2 to the stromal cells in the of the differentiation the and expression of the differentiation and in BMP2 a critical stromal in and a to the function of BMP2 in stromal a to BMP2 into stromal BMP2 and protein of BMP2 expression and signaling of stromal differentiation the expression of of the decidual in that signaling a critical role in stromal differentiation in the in that of BMP2 in the mouse to a in and of early pregnancy BMP2 and in the of signaling in during and in that and a of differentiation the of a and signaling pathways A that BMP2 and signaling pathways and in cells and expression of BMP2 and in in the uterine stromal during early a downstream of BMP2 signaling in mouse uterine stromal We the in stromal to that is induced in to BMP2 to a that the stromal of this is of the role of BMP2 signaling during of endometrial stromal the a in the of P a in the of during the of the to the stromal cells to into decidual cells during the of the differentiation of stromal cells into decidual is a and of is a decidual pregnancy of a in stromal cells in to and to the expression and function of BMP2 during this differentiation expression of BMP2 in stromal cells endometrial in the of the a expression of BMP2 in stromal cells decidualization. We that of BMP2 the differentiation in the endometrial stromal The expression of stromal differentiation and induced 2 in to this that of the stromal differentiation in in that a BMP2 and during uterine stromal differentiation in and is of to that a the expression of and in during the the of the of in is in the the the of decidualization. The progesterone (P) progesterone bone morphogenetic protein progesterone bone morphogenetic protein and in to uterine of A role of P is to induce differentiation of the endometrial stromal cells into decidual cells of the this differentiation process, is a and is the of to the uterine of The is the and differentiation of the stromal cells the implanting to the decidual of the The decidual cells to and that critical that and function during pregnancy of of P-induced signaling that participate in the formation and function of this remain poorly understood. is that the of the of P the progesterone in of role of in in the a mouse a of this of in the of a decidual and to support To is to the of that this during the differentiation To this a pathways to the and function We to the expression in the this the of that P of bone morphogenetic (BMP2), a of the TGFβ of We that BMP2 and in the uterine stroma in a decidual during early the that BMP2 is a of the stromal differentiation during decidualization. To the function of BMP2 in a in stromal cells mouse decidualization. this in that the BMP2 signaling a critical role in decidualization. and a of and in of of expression in the the endometrial stromal cells a differentiation process, during the of the of a of protein and in stromal cells The of in stromal differentiation remain this that BMP2 is induced in endometrial stromal cells during that a BMP2 and downstream in the BMP2 and in the of the and of The the of and of and the endometrial and endometrial to the the of in and the of and the of early of the the and endometrial to BMP2 and and stromal and BMP2 and of and of in of to the uterine and into uterine in and and The and the to the endometrial The in and in the the endometrial stromal The of the a in and cells a cells in The cells and of P and to mouse BMP2 and and The in the uterine stromal cells the of of of to and into BMP2 and in the of the and of The the of and of and the endometrial and endometrial to the the of in and the of and the of early of the the and endometrial to BMP2 and and stromal and BMP2 and of and of in of to the uterine and into uterine in and and The and the to the endometrial The in and in the the endometrial stromal The of the a in and cells a cells in The cells and of P and to mouse BMP2 and and The in the uterine stromal cells the of of of to and into a of in the the function during the in uterine expression in to the of pregnancy and during the The uterine to mouse We expression in the decidual in to of the bone morphogenetic (BMP2), a morphogen that a of and the of the the of and a BMP2 A to BMP2 in the of pregnancy in the uterine that the BMP2 is a downstream of in the decidual the expression of BMP2 protein in mouse during early pregnancy BMP2 expression in uterine in the BMP2 in the stromal cells the in the uterine of of pregnancy the BMP2 in the stromal cells in the of the in the cells of the stroma pregnancy to BMP2 expression in the stromal cells the of the of and that and BMP2 signaling We the expression of in in in the stromal cells of and of the expression in the decidual and The in the to the that BMP2 and in the uterine stroma during of in the role of signaling in uterine a mouse in stromal cells in of uterine stromal and and of of pregnancy and The and the to the stromal The stromal cells a and in the of the and of the cells to of decidual cells a and We the in the expression of and decidual protein of uterine stromal differentiation the of stromal to a in the expression of and and The and in a of uterine stromal cells in the BMP2 expression in stromal expression of BMP2 protein of The BMP2 expression a the of BMP2 signaling during stromal BMP2 to stromal and the differentiation of BMP2 to and We that of BMP2 the of the of cells A that the of in a and BMP2 that this morphogen stromal differentiation We a in the expression of in stromal cells in to of The stromal cells of cells that BMP2 stromal stromal to the differentiation of stromal cells in the of and of BMP2 and a of and in of of in of stromal cells and the of and of The of the in a The in expression of in the stromal cells of BMP2 The of expression that of is of in stromal cells in the of the signaling the in in the signaling to in to the BMP2 is to pathways protein in of BMP2 the of that BMP2 signaling in stromal cells during of the role of BMP2 stromal of stromal cells of and to the BMP2 cells a We that the cells BMP2 in BMP2 expression cells in BMP2 expression cells that the cells BMP2 a in BMP2 this expression of BMP2 decidualization. stromal cells BMP2 the of of BMP2 stromal cells and BMP2 BMP2 protein of and stromal cells and BMP2 the of this of BMP2 expression during stromal in of BMP2 in the stromal cells to a in expression of differentiation and the of in cells BMP2 that BMP2 expression is critical of the stromal differentiation during a of BMP2 during the downstream of BMP2 signaling during expression of uterine stromal cells BMP2 We that the expression of of BMP2 and of the expression in to To the uterine stromal cells and the expression of and cells a of expression in to BMP2 during stromal differentiation in the expression of and in to A of expression in to BMP2 a in the of of of BMP2 to the stromal the of to that a downstream of BMP2 signaling in uterine stromal is induced in decidual stromal cells in to stromal cells BMP2 and to and of in to cells BMP2 and to and to mouse stromal cells BMP2 to the stromal of to and stromal cells the of of in of expression stromal in stromal cells to the of this the of of expression a in the expression of differentiation and that is a critical of stromal of BMP2 and in during the and of the expression of BMP2 in endometrial stromal cells during in decidualization. stromal cells endometrial in the of the in and to in to a and We the of and protein during this in the expression of BMP2 during in a of this in stromal cells in to the early of the The of BMP2 The expression of BMP2 protein a of expression that is during stromal and expression that of BMP2 that the expression of BMP2 and induced during stromal in the is in the stromal cells expression and differentiation of endometrial stromal of stromal cells endometrial of The cells in The cells a P and cells of and to and of BMP2 in stromal cells during in decidualization. and and of and of stromal cells the and BMP2 and to and and cells and P and and BMP2 and of in the role of BMP2 in stromal differentiation BMP2 to endometrial stromal cells that to in the of and of the to a of and during the in the of and of BMP2 the to the expression of that of of a of in to BMP2 during stromal differentiation that a critical of in the in the and a signaling downstream BMP2 a of in the the function during the in uterine expression in to the of pregnancy and during the The uterine to mouse We expression in the decidual in to of the bone morphogenetic (BMP2), a morphogen that a of and We the of the the of and a BMP2 A to BMP2 in the of pregnancy in the uterine that the BMP2 is a downstream of in the decidual We the expression of BMP2 protein in mouse during early pregnancy BMP2 expression in uterine in the BMP2 in the stromal cells the in the uterine of of pregnancy the BMP2 in the stromal cells in the of the in the cells of the stroma pregnancy to BMP2 expression in the stromal cells the of the of and that and BMP2 signaling We the expression of in in in the stromal cells of and of the expression in the decidual and The in the to the that BMP2 and in the uterine stroma during decidualization. BMP2 of in the role of signaling in uterine a mouse in stromal cells in of uterine stromal and and of of pregnancy and The and the to the stromal The stromal cells a and in the of the and of the cells to of decidual cells a and We the in the expression of and decidual protein of uterine stromal differentiation the of stromal to a in the expression of and and The and in a of uterine stromal cells in the BMP2 expression in stromal expression of BMP2 protein of The BMP2 expression a To the of BMP2 signaling during stromal BMP2 to stromal and the differentiation of BMP2 to and We that of BMP2 the of the of cells A that the of in a and BMP2 that this morphogen stromal differentiation We a in the expression of in stromal cells in to of The stromal cells of cells that BMP2 stromal the signaling the in in the signaling to in to the BMP2 is to pathways protein in of BMP2 the of that BMP2 signaling in stromal cells during decidualization. BMP2 of the role of BMP2 stromal of stromal cells of and to the BMP2 cells a We that the cells BMP2 in BMP2 expression cells in BMP2 expression cells that the cells BMP2 a in BMP2 this expression We the of this of BMP2 expression during stromal in of BMP2 in the stromal cells to a in expression of differentiation and the of in cells BMP2 that BMP2 expression is critical of the stromal differentiation during decidualization. a of BMP2 during the downstream of BMP2 signaling during expression of uterine stromal cells BMP2 We that the expression of of BMP2 and of the expression in to To the uterine stromal cells and the expression of and cells a of expression in to BMP2 during stromal differentiation in the expression of and in to A of expression in to BMP2 a in the of of of BMP2 to the stromal the of to that a downstream of BMP2 signaling in uterine stromal of in of expression stromal in stromal cells to the of this the of of expression a in the expression of differentiation and that is a critical of stromal decidualization. of BMP2 and in during the and of the expression of BMP2 in endometrial stromal cells during in decidualization. stromal cells endometrial in the of the in and to in to a and We the of and protein during this in the expression of BMP2 during in a of this in stromal cells in to the early of the The of BMP2 The expression of BMP2 protein a of expression that is during stromal and expression that of BMP2 that the expression of BMP2 and induced during stromal in the is in the stromal cells decidualization. BMP2 and of in the role of BMP2 in stromal differentiation BMP2 to endometrial stromal cells that to in the of and of the to a of and during the in the of and of BMP2 the to the expression of that of of a of in to BMP2 during stromal differentiation that a critical of in the in the and a signaling downstream early P the of endometrial stromal cells into decidual a that is To the signaling pathways in the of the decidual of the expression to the expression is in mouse in to a this a signaling BMP2 and downstream of signaling to stromal The of this report is that this is during mouse and endometrial a of belonging to the TGFβ of to induce formation of and to a of and in a of during development in that to in mouse during the decidual of is in the cells of expression is in the stroma to the BMP2 is in the stromal cells the embryo. and in the decidual cells is the of in uterine and that of the in induced BMP2 that BMP2 expression is of that BMP2 is the of the expression is P in the expression of BMP2 and in the stromal cells during early pregnancy that this morphogen is a critical of decidualization. The of mouse stromal a role of BMP2 during the decidual We that of BMP2 to the stromal cells in the of the differentiation the and expression of the differentiation and in BMP2 a critical stromal in and a to the function of BMP2 in stromal a to BMP2 into stromal BMP2 and protein of BMP2 expression and signaling of stromal differentiation the expression of of the decidual in that signaling a critical role in stromal differentiation in the in that of BMP2 in the mouse to a in and of early pregnancy BMP2 and in the of signaling in during and in that and a of differentiation the of a and signaling pathways A that BMP2 and signaling pathways and in cells and expression of BMP2 and in in the uterine stromal during early a downstream of BMP2 signaling in mouse uterine stromal We the in stromal to that is induced in to BMP2 to a that the stromal of this is of the role of BMP2 signaling during of endometrial stromal the a in the of P a in the of during the of the to the stromal cells to into decidual cells during the of the differentiation of stromal cells into decidual is a and of is a decidual pregnancy of a in stromal cells in to and to the expression and function of BMP2 during this differentiation expression of BMP2 in stromal cells endometrial in the of the a expression of BMP2 in stromal cells decidualization. We that of BMP2 the differentiation in the endometrial stromal The expression of stromal differentiation and induced 2 in to this that of the stromal differentiation in in that a BMP2 and during uterine stromal differentiation in and is of to that a the expression of and in during the the of the of in is in the the the of decidualization. early P the of endometrial stromal cells into decidual a that is To the signaling pathways in the of the decidual of the expression to the expression is in mouse in to a this a signaling BMP2 and downstream of signaling to stromal The of this report is that this is during mouse and endometrial decidualization. a of belonging to the TGFβ of to induce formation of and to a of and in a of during development in that to in mouse during the decidual of is in the cells of expression is in the stroma to the BMP2 is in the stromal cells the embryo. and in the decidual cells is the of in uterine and that of the in induced BMP2 that BMP2 expression is of that BMP2 is the of the expression is P in the expression of BMP2 and in the stromal cells during early pregnancy that this morphogen is a critical of decidualization. The of mouse stromal a role of BMP2 during the decidual We that of BMP2 to the stromal cells in the of the differentiation the and expression of the differentiation and in BMP2 a critical stromal decidualization. We in and a to the function of BMP2 in stromal a to BMP2 into stromal BMP2 and protein of BMP2 expression and signaling of stromal differentiation the expression of of the decidual in that signaling a critical role in stromal differentiation in the in that of BMP2 in the mouse to a in and of early pregnancy BMP2 and in the of signaling in during and in that and a of differentiation the of a and signaling pathways A that BMP2 and signaling pathways and in cells and expression of BMP2 and in in the uterine stromal during early a downstream of BMP2 signaling in mouse uterine stromal We the in stromal to that is induced in to BMP2 to a that the stromal decidualization. of this is of the role of BMP2 signaling during of endometrial stromal the a in the of P a in the of during the of the to the stromal cells to into decidual cells during the of the differentiation of stromal cells into decidual is a and of is a decidual pregnancy The of a in stromal cells in to and to the expression and function of BMP2 during this differentiation expression of BMP2 in stromal cells endometrial in the of the a expression of BMP2 in stromal cells decidualization. We that of BMP2 the differentiation in the endometrial stromal The expression of stromal differentiation and induced 2 in to this that of the stromal differentiation in in that a BMP2 and during uterine stromal differentiation in and is of to that a the expression of and in during the the of the of in is in the the the of decidualization.