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Submitted on August 24, 2004
Accepted on October 27, 2004
Departments of Pediatrics, Cell & Developmental Biology, Pharmacology, Biochemistry and Cancer Biology, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Biochemistry & Molecular Biology, Mayo Clinic, Scottsdale, AZ 85259
* To whom correspondence should be addressed. E-mail: sk.dey{at}vanderbilt.edu.
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 particularly due to reduced uterine responsiveness to progesterone (P4) 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 (DIGE), we have identified an immunophilin FKBP52 as one of the Hoxa10 mediated signaling molecules in the uterus. We found that FKBP52, a co-chaperone protein known to influence steroid hormone receptor functions, is downregulated in stromal cells of Hoxa10-/- mice. More importantly, FKBP52 shows differential uterine cell-specific expression during the periimplantation period. While it is primarily expressed in the uterine epithelium on day 1 of pregnancy, the expression expands to the stroma on day 4 during the period of uterine receptivity and becomes localized to decidualizing stromal cells surrounding the implantation site on day 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 P4 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.
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