Steroid receptor coactivator 2 is essential for progesterone-dependent uterine function and mammary morphogenesis: Insights from the mouse—implications for the human

ABSTRACT Although the essential involvement of the progesterone receptor (PR) in female reproductive tissues is firmly established, the coregulators preferentially enlisted by PR to mediate its physiological effects have yet to be fully delineated. To further dissect the roles of members of the steroid receptor coactivator (SRC)/p160 family in PR-mediated reproductive processes in vivo, state-of-the-art cre-loxP engineering strategies were employed to generate a mouse model (PR Cre/+ SRC-2 flox/flox) in which SRC-2 function was abrogated only in cell lineages that express the PR. Fertility tests revealed that while ovarian activity was normal, PR Cre/+ SRC-2 flox/flox mouse uterine function was severely compromised. Absence of SRC-2 in PR-positive uterine cells was shown to contribute to an early block in embryo implantation, a phenotype not shared by SRC-1 or -3 knockout mice. In addition, histological and molecular analyses revealed an inability of the PR Cre/+ SRC-2 flox/flox mouse uterus to undergo the necessary cellular and molecular changes that precede complete P-induced decidual progression. Moreover, removal of SRC-1 in the PR Cre/+ SRC-2 flox/flox mouse uterus resulted in the absence of a decidual response, confirming that uterine SRC-2 and -1 cooperate in P-initiated transcriptional programs which lead to full decidualization. In the case of the mammary gland, whole-mount and histological analysis disclosed the absence of significant ductal side branching and alveologenesis in the hormone-treated PR Cre/+ SRC-2 flox/flox mammary gland, reinforcing an important role for SRC-2 in cellular proliferative changes that require PR. We conclude that SRC-2 is appropriated by PR in a subset of transcriptional cascades obligate for normal uterine and mammary morphogenesis and function.

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Steroid Receptor Coactivator 2: An Essential Coregulator of Progestin-Induced Uterine and Mammary Morphogenesis

Progestins and the Mammary Gland - Ernst Schering Foundation Symposium Proceedings ◽

10.1007/2789_2007_057 ◽

2007 ◽

pp. 55-76 ◽

Cited By ~ 1

Author(s):

A. Mukherjee ◽

P. Amato ◽

D. Craig-Allred ◽

F. J. DeMayo ◽

B. W. O'Malley ◽

...

Keyword(s):

Steroid Receptor ◽

Steroid Receptor Coactivator ◽

Mammary Morphogenesis

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The p160 Steroid Receptor Coactivator 2, SRC-2, Regulates Murine Endometrial Function and Regulates Progesterone-Independent and -Dependent Gene Expression

Endocrinology ◽

10.1210/en.2007-0122 ◽

2007 ◽

Vol 148 (9) ◽

pp. 4238-4250 ◽

Cited By ~ 37

Author(s):

Jae-Wook Jeong ◽

Kevin Y. Lee ◽

Sang Jun Han ◽

Bruce J. Aronow ◽

John P. Lydon ◽

...

Keyword(s):

Gene Expression ◽

Microarray Analysis ◽

Steroid Receptor ◽

Protein Signaling ◽

Endometrial Stromal Cells ◽

Steroid Receptor Coactivator ◽

Ovariectomized Mice ◽

Uterine Function ◽

Decidual Reaction ◽

The Impact

The role of the p160 steroid receptor coactivator 2 (SRC-2) in the regulation of uterine function and progesterone (P4) signaling was investigated by determining the expression pattern of SRC-2 in the murine uterus during pregnancy and the impact of SRC-2 ablation on uterine function and global uterine gene expression in response to progesterone. SRC-2 is expressed in the endometrial luminal and glandular epithelium from pregnancy d 0.5. SRC-2 is then expressed in the endometrial stroma on pregnancy d 2.5–3.5. Once the embryo is implanted, SRC-2 is expressed in the endometrial stromal cells in the secondary decidual zone. This compartmental expression of SRC-2 can be mimicked by treatment of ovariectomized mice with estrogen and P4. Ablation of SRC-2 in the uterus resulted in a significant reduction in the ability of the uterus to undergo a hormonally induced decidual reaction. Microarray analysis of RNA from uteri of wild-type and SRC-2−/− mice treated with vehicle or P4 showed that SRC-2 was involved in the ability of progesterone to repress specific genes. This microarray analysis also revealed that the uteri of SRC-2−/− mice showed alterations in genes involved in estrogen receptor, Wnt, and bone morphogenetic protein signaling. This analysis indicates that SRC-2 regulates uterine function by modulating the regulation of developmentally important signaling molecules and the ability of P4 to repress specific genes.

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