A Mouse Model to Dissect Progesterone Signaling in the Female Reproductive Tract and Mammary Gland

Overview

Journal Genesis

Specialties Biology
Molecular Biology

Date 2009 Dec 24

PMID 20029965

Citations 45

Authors

Rodrigo Fernandez-Valdivia

Jaewook Jeong

Atish Mukherjee

Selma M Soyal

Jie Li

Yan Ying

Francesco J DeMayo

John P Lydon

Affiliations

Soon will be listed here.

Abstract

Considering the regulatory complexities of progesterone receptor (PR) action throughout the female reproductive axis and mammary gland, we generated a mouse model that enables conditional ablation of PR function in a spatiotemporal specific manner. Exon 2 of the murine PR gene was floxed to generate a conditional PR allele (PR(flox)) in mice. Crossing the PR(flox/flox) mouse with the ZP3-cre transgenic demonstrated that the PR(flox) allele recombines to a PR null allele (PR(d)). Mice homozygous for the recombined null PR allele (PR(d/d)) exhibit uterine, ovarian, and mammary gland defects that phenocopy those of our previously described PR knockout (PRKO) model. Therefore, this conditional mouse model for PR ablation represents an invaluable resource with which to further define in a developmental and/or reproductive stage-specific manner the individual and integrative roles of distinct PR populations resident in multiple progesterone-responsive target sites.

Citing Articles

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References

Mulac-Jericevic B, Lydon J, DeMayo F, Conneely O . Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci U S A. 2003; 100(17):9744-9. PMC: 187836. DOI: 10.1073/pnas.1732707100. View

Soyal S, Mukherjee A, Lee K, Li J, Li H, DeMayo F . Cre-mediated recombination in cell lineages that express the progesterone receptor. Genesis. 2005; 41(2):58-66. DOI: 10.1002/gene.20098. View

Phelps S, Lydon J, OMalley B, Crews D . Regulation of male sexual behavior by progesterone receptor, sexual experience, and androgen. Horm Behav. 1999; 34(3):294-302. DOI: 10.1006/hbeh.1998.1485. View

Ismail P, Li J, DeMayo F, OMalley B, Lydon J . A novel LacZ reporter mouse reveals complex regulation of the progesterone receptor promoter during mammary gland development. Mol Endocrinol. 2002; 16(11):2475-89. DOI: 10.1210/me.2002-0169. View

Karas R, van Eickels M, Lydon J, Roddy S, Kwoun M, Aronovitz M . A complex role for the progesterone receptor in the response to vascular injury. J Clin Invest. 2001; 108(4):611-8. PMC: 209395. DOI: 10.1172/JCI11374. View

Brisken C, Park S, Vass T, Lydon J, OMalley B, Weinberg R . A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc Natl Acad Sci U S A. 1998; 95(9):5076-81. PMC: 20216. DOI: 10.1073/pnas.95.9.5076. View

Lydon J, Demayo F, FUNK C, Mani S, Hughes A, Montgomery Jr C . Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995; 9(18):2266-78. DOI: 10.1101/gad.9.18.2266. View

Tong W, Pollard J . Progesterone inhibits estrogen-induced cyclin D1 and cdk4 nuclear translocation, cyclin E- and cyclin A-cdk2 kinase activation, and cell proliferation in uterine epithelial cells in mice. Mol Cell Biol. 1999; 19(3):2251-64. PMC: 84018. DOI: 10.1128/MCB.19.3.2251. View

Tibbetts T, OMalley B, Conneely O . Mutual and intercompartmental regulation of estrogen receptor and progesterone receptor expression in the mouse uterus. Biol Reprod. 1998; 59(5):1143-52. DOI: 10.1095/biolreprod59.5.1143. View

10.

Lydon J, Ge G, Kittrell F, Medina D, OMalley B . Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function. Cancer Res. 1999; 59(17):4276-84. View

11.

Lee K, Jeong J, Kwak I, Yu C, Lanske B, Soegiarto D . Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nat Genet. 2006; 38(10):1204-9. DOI: 10.1038/ng1874. View

12.

Lewandoski M, Wassarman K, Martin G . Zp3-cre, a transgenic mouse line for the activation or inactivation of loxP-flanked target genes specifically in the female germ line. Curr Biol. 1997; 7(2):148-51. DOI: 10.1016/s0960-9822(06)00059-5. View

13.

Zhu L, Pollard J . Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling. Proc Natl Acad Sci U S A. 2007; 104(40):15847-51. PMC: 2000402. DOI: 10.1073/pnas.0705749104. View

14.

Kurita T, Young P, Brody J, Lydon J, OMalley B, Cunha G . Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis. Endocrinology. 1998; 139(11):4708-13. DOI: 10.1210/endo.139.11.6317. View

15.

Chen B, Pan H, Zhu L, Deng Y, Pollard J . Progesterone inhibits the estrogen-induced phosphoinositide 3-kinase-->AKT-->GSK-3beta-->cyclin D1-->pRB pathway to block uterine epithelial cell proliferation. Mol Endocrinol. 2005; 19(8):1978-90. DOI: 10.1210/me.2004-0274. View

16.

Farley F, Soriano P, Steffen L, Dymecki S . Widespread recombinase expression using FLPeR (flipper) mice. Genesis. 2000; 28(3-4):106-10. View

17.

Schneider J, Burgess C, Sleiter N, DonCarlos L, Lydon J, OMalley B . Enhanced sexual behaviors and androgen receptor immunoreactivity in the male progesterone receptor knockout mouse. Endocrinology. 2005; 146(10):4340-8. DOI: 10.1210/en.2005-0490. View

18.

Kurihara I, Lee D, Petit F, Jeong J, Lee K, Lydon J . COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity. PLoS Genet. 2007; 3(6):e102. PMC: 1892047. DOI: 10.1371/journal.pgen.0030102. View

19.

Lee K, Jeong J, Wang J, Ma L, Martin J, Tsai S . Bmp2 is critical for the murine uterine decidual response. Mol Cell Biol. 2007; 27(15):5468-78. PMC: 1952078. DOI: 10.1128/MCB.00342-07. View

20.

Pan H, Deng Y, Pollard J . Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing. Proc Natl Acad Sci U S A. 2006; 103(38):14021-6. PMC: 1599905. DOI: 10.1073/pnas.0601271103. View