Activin-Like Kinase 2 Functions in Peri-implantation Uterine Signaling in Mice and Humans

Caterina Clementi, Swamy K. Tripurani, Michael J. Large, Mark A. Edson, Chad J. Creighton, Shannon Hawkins, Ertug Kovanci, Vesa Kaartinen, John P. Lydon, Stephanie A. Pangas, Francesco J. DeMayo, Martin M. Matzuk

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Implantation of a blastocyst in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the uterus of pregnant mice, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing mice carrying a conditional ablation of Alk2 in the uterus (Alk2 cKO mice). In the absence of ALK2, embryos demonstrate delayed invasion into the uterine epithelium and stroma, and upon implantation, stromal cells fail to undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein β (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of CEBPB in the stroma to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (hESC) and discovered that ablation of ALK2 alters hESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing hESC confirmed that BMP signaling proteins, SMAD1/5, directly regulate expression of CEBPB by binding a distinct regulatory sequence in the 3′ UTR of this gene; CEBPB, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate peri-implantation in rodents and primates and, for the first time, uncovers a linear pathway of BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization.

Original languageEnglish (US)
Article numbere1003863
JournalPLoS Genetics
Volume9
Issue number11
DOIs
StatePublished - Nov 2013
Externally publishedYes

Fingerprint

activins
Activins
bone morphogenetic proteins
stromal cells
Stromal Cells
phosphotransferases (kinases)
Phosphotransferases
protein
uterus
mice
Uterus
Bone Morphogenetic Proteins
bone
Progesterone Receptors
Type I Bone Morphogenetic Protein Receptors
Bone Morphogenetic Protein Receptors
CCAAT-Enhancer-Binding Proteins
ablation
embryo implantation
regulatory sequences

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Clementi, C., Tripurani, S. K., Large, M. J., Edson, M. A., Creighton, C. J., Hawkins, S., ... Matzuk, M. M. (2013). Activin-Like Kinase 2 Functions in Peri-implantation Uterine Signaling in Mice and Humans. PLoS Genetics, 9(11), [e1003863]. https://doi.org/10.1371/journal.pgen.1003863

Activin-Like Kinase 2 Functions in Peri-implantation Uterine Signaling in Mice and Humans. / Clementi, Caterina; Tripurani, Swamy K.; Large, Michael J.; Edson, Mark A.; Creighton, Chad J.; Hawkins, Shannon; Kovanci, Ertug; Kaartinen, Vesa; Lydon, John P.; Pangas, Stephanie A.; DeMayo, Francesco J.; Matzuk, Martin M.

In: PLoS Genetics, Vol. 9, No. 11, e1003863, 11.2013.

Research output: Contribution to journalArticle

Clementi, C, Tripurani, SK, Large, MJ, Edson, MA, Creighton, CJ, Hawkins, S, Kovanci, E, Kaartinen, V, Lydon, JP, Pangas, SA, DeMayo, FJ & Matzuk, MM 2013, 'Activin-Like Kinase 2 Functions in Peri-implantation Uterine Signaling in Mice and Humans', PLoS Genetics, vol. 9, no. 11, e1003863. https://doi.org/10.1371/journal.pgen.1003863
Clementi, Caterina ; Tripurani, Swamy K. ; Large, Michael J. ; Edson, Mark A. ; Creighton, Chad J. ; Hawkins, Shannon ; Kovanci, Ertug ; Kaartinen, Vesa ; Lydon, John P. ; Pangas, Stephanie A. ; DeMayo, Francesco J. ; Matzuk, Martin M. / Activin-Like Kinase 2 Functions in Peri-implantation Uterine Signaling in Mice and Humans. In: PLoS Genetics. 2013 ; Vol. 9, No. 11.
@article{6477f401554248afb7d262be686c8669,
title = "Activin-Like Kinase 2 Functions in Peri-implantation Uterine Signaling in Mice and Humans",
abstract = "Implantation of a blastocyst in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the uterus of pregnant mice, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing mice carrying a conditional ablation of Alk2 in the uterus (Alk2 cKO mice). In the absence of ALK2, embryos demonstrate delayed invasion into the uterine epithelium and stroma, and upon implantation, stromal cells fail to undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein β (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of CEBPB in the stroma to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (hESC) and discovered that ablation of ALK2 alters hESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing hESC confirmed that BMP signaling proteins, SMAD1/5, directly regulate expression of CEBPB by binding a distinct regulatory sequence in the 3′ UTR of this gene; CEBPB, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate peri-implantation in rodents and primates and, for the first time, uncovers a linear pathway of BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization.",
author = "Caterina Clementi and Tripurani, {Swamy K.} and Large, {Michael J.} and Edson, {Mark A.} and Creighton, {Chad J.} and Shannon Hawkins and Ertug Kovanci and Vesa Kaartinen and Lydon, {John P.} and Pangas, {Stephanie A.} and DeMayo, {Francesco J.} and Matzuk, {Martin M.}",
year = "2013",
month = "11",
doi = "10.1371/journal.pgen.1003863",
language = "English (US)",
volume = "9",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "11",

}

TY - JOUR

T1 - Activin-Like Kinase 2 Functions in Peri-implantation Uterine Signaling in Mice and Humans

AU - Clementi, Caterina

AU - Tripurani, Swamy K.

AU - Large, Michael J.

AU - Edson, Mark A.

AU - Creighton, Chad J.

AU - Hawkins, Shannon

AU - Kovanci, Ertug

AU - Kaartinen, Vesa

AU - Lydon, John P.

AU - Pangas, Stephanie A.

AU - DeMayo, Francesco J.

AU - Matzuk, Martin M.

PY - 2013/11

Y1 - 2013/11

N2 - Implantation of a blastocyst in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the uterus of pregnant mice, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing mice carrying a conditional ablation of Alk2 in the uterus (Alk2 cKO mice). In the absence of ALK2, embryos demonstrate delayed invasion into the uterine epithelium and stroma, and upon implantation, stromal cells fail to undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein β (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of CEBPB in the stroma to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (hESC) and discovered that ablation of ALK2 alters hESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing hESC confirmed that BMP signaling proteins, SMAD1/5, directly regulate expression of CEBPB by binding a distinct regulatory sequence in the 3′ UTR of this gene; CEBPB, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate peri-implantation in rodents and primates and, for the first time, uncovers a linear pathway of BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization.

AB - Implantation of a blastocyst in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the uterus of pregnant mice, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing mice carrying a conditional ablation of Alk2 in the uterus (Alk2 cKO mice). In the absence of ALK2, embryos demonstrate delayed invasion into the uterine epithelium and stroma, and upon implantation, stromal cells fail to undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein β (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of CEBPB in the stroma to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (hESC) and discovered that ablation of ALK2 alters hESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing hESC confirmed that BMP signaling proteins, SMAD1/5, directly regulate expression of CEBPB by binding a distinct regulatory sequence in the 3′ UTR of this gene; CEBPB, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate peri-implantation in rodents and primates and, for the first time, uncovers a linear pathway of BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization.

UR - http://www.scopus.com/inward/record.url?scp=84888264302&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84888264302&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1003863

DO - 10.1371/journal.pgen.1003863

M3 - Article

VL - 9

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 11

M1 - e1003863

ER -