Generation of Mice with Either Ubiquitous or Corpus Luteum-Specific Expression of the Long Form of the Prolactin Receptor Reveals That Both Isoforms of the Receptor Are Required for Normal Female Fertility

JAMIE A. LE, HEATHER M. WILSON, JIFANG MAO, AURORA SHEHU, Y. SANGEETA DEVI, JULIA HALPERIN, TETLEY AGUILAR, ANITA SEIBOLD, AND GEULA GIBORI

Pittsburgh. USA

Congreso; Society for the Study of Reproduction 42nd Annual Meeting; 2009

We have previously established that PRL does not rescue thecorpus luteum (CL) and causes premature ovarian failure in miceexpressing only the short form of the PRL receptor (PRLRS).In this investigation, we examined whether PRL signaling solelythrough the long form of the receptor (PRLRL) can sustain fertility.Using PRLR null mice, we generated transgenic mice expressingPRLRL alone and discovered that the females are sterile, butthe males are fertile and become obese with age due to severeaccumulation of epididymal fat. Female PRLRL mice have normalestrus cycles, mating behavior, and ovulate normally. PRLRLembryos transplanted to wild type mothers are born, indicatingthat the infertility defect in PRLRL female mice is maternal.We found no difference in LH or FSH levels in PRLRL mice, yetestradiol levels are dramatically elevated. Although CLs arefound through day 5 of pregnancy and PRL can induce Stat5 phosphorylationin ovaries of PRLRL mice, implantation does not occur. Dailyadministration of progesterone could not totally rescue pregnancyand only few embryos are found alive by C-section. A severedefect in decidualization is observed despite progesterone treatmentthrough day 9 of pregnancy. To determine whether the infertilitydefect in PRLRL mice is a result of ubiquitous expression ofthis receptor, we generated transgenic mice expressing PRLRLspecifically in the CL (CL-PRLRL) using the PRAP-17BHSD7 promoter.To our surprise, these mice are also infertile and, similarlyto the PRLRL mice, have normal estrus cycle, mating behaviors,ovulation rate, and CL formation, yet implantation does notoccur. Transplantation of CL-PRLRL embryos to wild type mothersled to normal birth of pups and progesterone treatment of CL-PRLRLmice could rescue pregnancy. In summary, we have succeeded atgenerating transgenic mice expressing PRLRL either in the wholeanimal or specifically in the CL and demonstrated that althoughPRL can activate the Stat pathway through PRLRL, it is unableto sustain progesterone production, but rather induces highlevels of estradiol and causes a decidualization defect. Moreover,we have found that while female mice are sterile, male miceare fertile and PRL signaling exclusively through PRLRL caninduce fat deposition in males. The results of this investigationclearly indicate that PRLRL alone is unable to support normalovarian function and that both isoforms of the receptor arerequired for normal female fertility. Our finding that PRLRLtransgenic mice on the wild type background are fertile furtherindicates that both PRLRS and PRLRL are required for maintenanceof pregnancy. Supported by NIH HD12356 and HD11119 (GG), T32HL007692 (JL & AS) and APS fellowship (JH).