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

• DOI: 10.1371/journal.pgen.1003863
• Publication Date: 2013-11-14T22:31:20Z
• Authors: Caterina Clementi; Swamy K. Tripurani; Michael J. Large; Mark A. Edson; Chad J. Creighton; Shannon M. Hawkins; Ertug Kovanci; Vesa Kaartinen; John P. Lydon; Stephanie A. Pangas; Francesco J. DeMayo; Martin M. Matzuk
• Keywords: Decidualization; Activin receptor

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