Decreased epithelial progesterone receptor A at the window of receptivity is required for preparation of the endometrium for embryo attachment†

Abstract The precise timing of progesterone signaling through its cognate receptor, the progesterone receptor (PGR), is critical for the establishment and maintenance of pregnancy. Loss of PGR expression in the murine uterine epithelium during the preimplantation period is a marker for uterine receptivity and embryo attachment. We hypothesized that the decrease in progesterone receptor A (PGRA) expression is necessary for successful embryo implantation. To test this hypothesis, a mouse model constitutively expressing PGRA (mPgrA LsL/+) was generated. Expression of PGRA in all uterine compartments (Pgrcre ) or uterine epithelium (Wnt7acre ) resulted in infertility with defects in embryo attachment and stromal decidualization. Expression of critical PGRA target genes, indian hedgehog, and amphiregulin (Areg), wasmaintained through the window of receptivity while the estrogen receptor target gene, the leukemia inhibitory factor (Lif), a key regulator of embryo receptivity, was decreased. Transcriptomic and cistromic analyses of the mouse uterus at day 4.5 of pregnancy identified an altered group of genes regulating molecular transport in the control of fluid and ion levels within the uterine interstitial space. Additionally, LIF and its cognate receptor, the leukemia inhibitory factor receptor (LIFR), exhibited PGR-binding events in regions upstream of the transcriptional start sites, suggesting PGRA is inhibiting transcription at these loci. Therefore, downregulation of the PGRA isoform at the window of receptivity is necessary for the attenuation of hedgehog signaling, transcriptional activation of LIF signaling, and modulation of solutes and fluid, producing a receptive environment for the attaching embryo. Summary Sentence Expression of PGRA at the window of receptivity transcriptionally represses LIF signaling and aberrantly regulates hedgehog and solute signaling rendering the uterus unreceptive to the implanting embryo.

[1]  X. Su,et al.  Thiazide-sensitive Na+-Cl- cotransporter: genetic polymorphisms and human diseases. , 2015, Acta biochimica et biophysica Sinica.

[2]  María Castañeda-Bueno,et al.  Ovarian hormones and prolactin increase renal NaCl cotransporter phosphorylation. , 2015, American journal of physiology. Renal physiology.

[3]  C. Stewart,et al.  The LIF-Mediated Molecular Signature Regulating Murine Embryo Implantation1 , 2014, Biology of reproduction.

[4]  F. DeMayo,et al.  Progesterone receptor signaling in the initiation of pregnancy and preservation of a healthy uterus. , 2014, The International journal of developmental biology.

[5]  Dan Zhang,et al.  Ion/water channels for embryo implantation barrier. , 2014, Physiology.

[6]  A. Warren,et al.  A role for two-pore potassium (K2P) channels in endometrial epithelial function , 2013, Journal of cellular and molecular medicine.

[7]  S. Dey,et al.  Mechanisms of implantation: strategies for successful pregnancy , 2012, Nature Medicine.

[8]  Xin-Mei Liu,et al.  Activation of the epithelial Na+ channel triggers prostaglandin E2 release and production required for embryo implantation , 2012, Nature Medicine.

[9]  R. Behringer,et al.  Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  S. Dey,et al.  Conditional deletion of Msx homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity. , 2011, Developmental cell.

[11]  K. Korach,et al.  Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses , 2010, Proceedings of the National Academy of Sciences.

[12]  K. Kaestner,et al.  Foxa2 Is Essential for Mouse Endometrial Gland Development and Fertility1 , 2010, Biology of reproduction.

[13]  M. Tsai,et al.  Generation of ES cells for conditional expression of nuclear receptors and coregulators in vivo. , 2010, Molecular endocrinology.

[14]  L. D. White,et al.  Constitutive Activation of Smoothened Leads to Female Infertility and Altered Uterine Differentiation in the Mouse1 , 2010, Biology of reproduction.

[15]  T. Spencer,et al.  Progesterone and interferon tau regulate leukemia inhibitory factor receptor and IL6ST in the ovine uterus during early pregnancy. , 2009, Reproduction.

[16]  E. Jeung,et al.  Uterine TRPV6 expression during the estrous cycle and pregnancy in a mouse model. , 2007, American journal of physiology. Endocrinology and metabolism.

[17]  C. Murphy,et al.  Aquaporins are upregulated in glandular epithelium at the time of implantation in the rat , 2007, Journal of Molecular Histology.

[18]  A. deFazio,et al.  Overlapping and distinct expression of progesterone receptors A and B in mouse uterus and mammary gland during the estrous cycle. , 2006, Endocrinology.

[19]  D. Edwards,et al.  Progesterone receptor isoforms A and B differentially regulate MUC1 expression in uterine epithelial cells. , 2006, Molecular endocrinology.

[20]  Sudhansu K. Dey,et al.  Roadmap to embryo implantation: clues from mouse models , 2006, Nature Reviews Genetics.

[21]  William D Mosher,et al.  Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth. , 2005, Vital and health statistics. Series 23, Data from the National Survey of Family Growth.

[22]  C. Burger,et al.  Progesterone-Induced Inhibition of Growth and Differential Regulation of Gene Expression in PRA- and/or PRB-Expressing Endometrial Cancer Cell Lines , 2005, The Journal of the Society for Gynecologic Investigation: JSGI.

[23]  J. Li,et al.  Cre‐mediated recombination in cell lineages that express the progesterone receptor , 2005, Genesis.

[24]  H. Chan,et al.  Differential expression and localization of CFTR and ENaC in mouse endometrium during pre‐implantation , 2004, Cell biology international.

[25]  K. Korach,et al.  Estrogen receptor knockout mice as a model for endocrine research. , 2004, ILAR journal.

[26]  M. Hediger,et al.  Epithelial Ca2+ entry channels: transcellular Ca2+ transport and beyond , 2003, The Journal of physiology.

[27]  F. DeMayo,et al.  Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Ju Gao,et al.  Aquaporin water channel genes are differentially expressed and regulated by ovarian steroids during the periimplantation period in the mouse. , 2003, Endocrinology.

[29]  J. Geraedts,et al.  Conception to ongoing pregnancy: the 'black box' of early pregnancy loss. , 2002, Human reproduction update.

[30]  F. DeMayo,et al.  Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. , 2000, Science.

[31]  S. Dey,et al.  Differential uterine expression of estrogen and progesterone receptors correlates with uterine preparation for implantation and decidualization in the mouse. , 1999, Endocrinology.

[32]  D. Carson,et al.  Mucin expression and function in the female reproductive tract. , 1998, Human reproduction update.

[33]  B. O’Malley,et al.  Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. , 1995, Genes & development.

[34]  B. O’Malley,et al.  Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. , 1993, Molecular endocrinology.

[35]  C. Stewart,et al.  Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor , 1992, Nature.

[36]  L. Martin,et al.  Endocrine control of the timing of endometrial sensitivity to a decidual stimulus. , 1972, Biology of reproduction.