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Biol Reprod. 2017 Jan 1;97(6):822-834. doi: 10.1093/biolre/iox143.

Med12 regulates ovarian steroidogenesis, uterine development and maternal effects in the mammalian egg.

Author information

1
Tsinghua MD Program, Tsinghua University School of Medicine, Beijing, China.
2
Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.
3
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
4
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
5
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Abstract

The transcriptional factor MED12 is part of the essential mediator transcriptional complex that acts as a transcriptional coactivator in all eukaryotes. Missense gain-of-function mutations in human MED12 are associated with uterine leiomyomas, yet the role of MED12 deficiency in tumorigenesis and reproductive biology has not been fully explored. We generated a Med12 reproductive conditional knockout mouse model to evaluate its role in uterine mesenchyme, granulosa cells, and oocytes. Mice heterozygous for Med12 deficiency in granulosa cells and uterus (Med12fl/+ Amhr2-Cre) were subfertile, while mice homozygous for Med12 deficiency in granulosa cells and uterus (Med12fl/fl Amhr2-Cre) were infertile. Morphological and histological analysis of the Med12fl/fl Amhr2-Cre reproductive tract revealed atrophic uteri and hyperchromatic granulosa cells with disrupted expression of Lhcgr, Esr1, and Esr2. Med12fl/fl Amhr2-Cre mice estrous cycle was disrupted, and serum analysis showed blunted rise in estradiol in response to pregnant mare serum gonadotropin. Uterine atrophy was partially rescued by exogenous steroid supplementation with dysregulation of Notch1 and Smo expression in steroid supplemented Med12fl/fl Amhr2-Cre uteri, indicating intrinsic uterine defects. Oocyte-specific ablation of Med12 caused infertility without disrupting normal folliculogenesis and ovulation, consistent with maternal effects of Med12 in early embryo development. These results show the critical importance of Med12 in reproductive tract development and that Med12 loss of function does not cause tumorigenesis in reproductive tissues.

KEYWORDS:

Med12; infertility; ovary; uterus

PMID:
29126187
PMCID:
PMC6248388
DOI:
10.1093/biolre/iox143
[Indexed for MEDLINE]
Free PMC Article

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