Proteomic analysis identifies immunophilin FK506 binding protein 4 (FKBP52) as a downstream target of Hoxa10 in the periimplantation mouse uterus.
The process of implantation absolutely requires synchronized development of the blastocyst to implantation competency, differentiation of the uterus to the receptive state, and a reciprocal dialogue between the blastocyst and uterine luminal epithelium. Genetic and molecular approaches have identified several signaling pathways that are critical to this process. The transcription factor Hoxa10 is one such critical player in implantation. Hoxa10-/- female mice have implantation and decidualization failure due specifically to reduced uterine responsiveness to progesterone and defective stromal cell proliferation during uterine receptivity and implantation. However, the downstream signaling pathways of Hoxa10 in these events remain largely unknown. Using the proteomics approach of difference gel electrophoresis, we have identified an immunophilin FKBP52 (FK506 binding protein 4) as one of the Hoxa10-mediated signaling molecules in the uterus. We found that FKBP52, a cochaperone protein known to influence steroid hormone receptor functions, is down-regulated in stromal cells of Hoxa10-/- mice. More importantly, FKBP52 shows differential uterine cell-specific expression during the periimplantation period. Whereas it is primarily expressed in the uterine epithelium on d 1 of pregnancy, the expression expands to the stroma on d 4 during the period of uterine receptivity and becomes localized to decidualizing stromal cells surrounding the implantation site on d 5. This suggests that FKBP52 is important for the attainment of uterine receptivity and implantation. Furthermore, FKBP52 shows differential cell-specific expression in the uterus in response to progesterone and/or estrogen consistent with its expression patterns during the periimplantation period. Collectively, these results and the female infertility phenotype of FKBP52 suggest that a Hoxa10-FKBP52 signaling axis is critical to uterine receptivity and implantation.
Daikoku
Takiko
T
Department of Pediatrics and Cancer Biology, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Tranguch
Susanne
S
Friedman
David B
DB
Das
Sanjoy K
SK
Smith
David F
DF
Dey
Sudhansu K
SK
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019992:Databases as Topic; D003893:Desmin / Q000378:metabolism; D015536:Down-Regulation; D015180:Electrophoresis, Gel, Two-Dimensional; D004967:Estrogens / Q000378:metabolism; D005260:Female; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007247:Infertility, Female; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D011374:Progesterone / Q000378:metabolism; D011485:Protein Binding; D040901:Proteomics / Q000379:methods*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D015854:Up-Regulation; D014599:Uterus / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D003893:Desmin; D004967:Estrogens; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D014746:Vimentin; C092119:Hoxa10 protein, mouse; D011374:Progesterone; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4