FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific.
Immunophilin FKBP52 serves as a cochaperone to govern normal progesterone (P(4)) receptor (PR) function. Using Fkbp52(-/-) mice, we show intriguing aspects of uterine P(4)/PR signaling during pregnancy. Implantation failure is the major phenotype found in these null females, which is conserved on both C57BL6/129 and CD1 backgrounds. However, P(4) supplementation rescued implantation and subsequent decidualization in CD1, but not C57BL6/129, null females. Surprisingly, experimentally induced decidualization in the absence of blastocysts failed in Fkbp52(-/-) mice on either background even with P(4) supplementation, suggesting that embryonic signals complement uterine signaling for this event. Another interesting finding was that while P(4) at higher than normal pregnancy levels conferred PR signaling sufficient for implantation in CD1 null females, these levels were inefficient in maintaining pregnancy to full term. However, elevating P(4) levels further restored PR signaling to a level optimal for successful term pregnancy with normal litter size. Collectively, the results show that the indispensability of FKBP52 in uterine P(4)/PR signaling is a function of genetic disparity and is pregnancy stage specific. Since there is evidence for a correlation between P(4) supplementation and reduced risks of P(4)-resistant recurrent miscarriages and remission of endometriosis, these findings have clinical implications for genetically diverse populations of women.
Tranguch
Susanne
S
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232-2678, USA.
Wang
Haibin
H
Daikoku
Takiko
T
Xie
Huirong
H
Smith
David F
DF
Dey
Sudhansu K
SK
D000818:Animals; D001755:Blastocyst / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance; D004624:Embryo Transfer; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism*
D011980:Receptors, Progesterone; D011374:Progesterone; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4