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Perturbing the cellular levels of steroid receptor coactivator-2 impairs murine endometrial function.

Szwarc MM, Kommagani R, Jeong JW, Wu SP, Tsai SY, Tsai MJ, O'Malley BW, DeMayo FJ, Lydon JP - PLoS ONE (2014)

Bottom Line: As pleiotropic coregulators, members of the p160/steroid receptor coactivator (SRC) family control a broad spectrum of transcriptional responses that underpin a diverse array of physiological and pathophysiological processes.Because of their potent coregulator properties, strict controls on SRC expression levels are required to maintain normal tissue functionality.This deficiency is significant since SRC involvement in many of these disorders is based on unscheduled increases in the levels (rather than the absence) of SRC expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.

ABSTRACT
As pleiotropic coregulators, members of the p160/steroid receptor coactivator (SRC) family control a broad spectrum of transcriptional responses that underpin a diverse array of physiological and pathophysiological processes. Because of their potent coregulator properties, strict controls on SRC expression levels are required to maintain normal tissue functionality. Accordingly, an unwarranted increase in the cellular levels of SRC members has been causally linked to the initiation and/or progression of a number of clinical disorders. Although knockout mouse models have underscored the critical non-redundant roles for each SRC member in vivo, there are surprisingly few mouse models that have been engineered to overexpress SRCs. This deficiency is significant since SRC involvement in many of these disorders is based on unscheduled increases in the levels (rather than the absence) of SRC expression. To address this deficiency, we used recent mouse technology that allows for the targeted expression of human SRC-2 in cells which express the progesterone receptor. Through cre-loxP recombination driven by the endogenous progesterone receptor promoter, a marked elevation in expression levels of human SRC-2 was achieved in endometrial cells that are positive for the progesterone receptor. As a result of this increase in coregulator expression, female mice are severely subfertile due to a dysfunctional uterus, which exhibits a hypersensitivity to estrogen exposure. Our findings strongly support the proposal from clinical observations that increased levels of SRC-2 are causal for a number of endometrial disorders which compromise fertility. Future studies will use this mouse model to decipher the molecular mechanisms that underpin the endometrial defect. We believe such mechanistic insight may provide new molecular descriptors for diagnosis, prognosis, and/or therapy in the clinical management of female infertility.

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Decidualization is severely impaired in the SRC-2:OE uterus.(A) Schematic showing the hormone regimen used to elicit the decidual response in the uterus of an ovariectomized mouse. (B) Gross morphology of uteri from the SRC-2LSL and SRC-2:OE mouse following the hormone treatment protocol shown in (A); S and C denote stimulated and control horn respectively. Scale bar applies to both panels. (C) Bar graph displays the wet weight ratio of stimulated horn over contralateral control horn for the SRC-2LSL and SRC-2:OE uterus.
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pone-0098664-g006: Decidualization is severely impaired in the SRC-2:OE uterus.(A) Schematic showing the hormone regimen used to elicit the decidual response in the uterus of an ovariectomized mouse. (B) Gross morphology of uteri from the SRC-2LSL and SRC-2:OE mouse following the hormone treatment protocol shown in (A); S and C denote stimulated and control horn respectively. Scale bar applies to both panels. (C) Bar graph displays the wet weight ratio of stimulated horn over contralateral control horn for the SRC-2LSL and SRC-2:OE uterus.

Mentions: To determine whether the subfertility phenotype exhibited by the SRC-2:OE female is caused by a defect in endometrial decidualization, an established hormone treatment protocol applied to ovariectomized mice was used to elicit an endometrial deciduogenic response (Fig. 6A). At the gross morphological level, Fig. 6B and C clearly show that the signature deciduogenic response is triggered in the stimulated left uterine horn of the SRC-2LSL mouse; however, an equivalent response is not achieved in the similarly treated uterine horn of the SRC-2:OE mouse. These results indicate that perturbing the levels of SRC-2 expression adversely affects the ability of the endometrium to decidualize.


Perturbing the cellular levels of steroid receptor coactivator-2 impairs murine endometrial function.

Szwarc MM, Kommagani R, Jeong JW, Wu SP, Tsai SY, Tsai MJ, O'Malley BW, DeMayo FJ, Lydon JP - PLoS ONE (2014)

Decidualization is severely impaired in the SRC-2:OE uterus.(A) Schematic showing the hormone regimen used to elicit the decidual response in the uterus of an ovariectomized mouse. (B) Gross morphology of uteri from the SRC-2LSL and SRC-2:OE mouse following the hormone treatment protocol shown in (A); S and C denote stimulated and control horn respectively. Scale bar applies to both panels. (C) Bar graph displays the wet weight ratio of stimulated horn over contralateral control horn for the SRC-2LSL and SRC-2:OE uterus.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048228&req=5

pone-0098664-g006: Decidualization is severely impaired in the SRC-2:OE uterus.(A) Schematic showing the hormone regimen used to elicit the decidual response in the uterus of an ovariectomized mouse. (B) Gross morphology of uteri from the SRC-2LSL and SRC-2:OE mouse following the hormone treatment protocol shown in (A); S and C denote stimulated and control horn respectively. Scale bar applies to both panels. (C) Bar graph displays the wet weight ratio of stimulated horn over contralateral control horn for the SRC-2LSL and SRC-2:OE uterus.
Mentions: To determine whether the subfertility phenotype exhibited by the SRC-2:OE female is caused by a defect in endometrial decidualization, an established hormone treatment protocol applied to ovariectomized mice was used to elicit an endometrial deciduogenic response (Fig. 6A). At the gross morphological level, Fig. 6B and C clearly show that the signature deciduogenic response is triggered in the stimulated left uterine horn of the SRC-2LSL mouse; however, an equivalent response is not achieved in the similarly treated uterine horn of the SRC-2:OE mouse. These results indicate that perturbing the levels of SRC-2 expression adversely affects the ability of the endometrium to decidualize.

Bottom Line: As pleiotropic coregulators, members of the p160/steroid receptor coactivator (SRC) family control a broad spectrum of transcriptional responses that underpin a diverse array of physiological and pathophysiological processes.Because of their potent coregulator properties, strict controls on SRC expression levels are required to maintain normal tissue functionality.This deficiency is significant since SRC involvement in many of these disorders is based on unscheduled increases in the levels (rather than the absence) of SRC expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.

ABSTRACT
As pleiotropic coregulators, members of the p160/steroid receptor coactivator (SRC) family control a broad spectrum of transcriptional responses that underpin a diverse array of physiological and pathophysiological processes. Because of their potent coregulator properties, strict controls on SRC expression levels are required to maintain normal tissue functionality. Accordingly, an unwarranted increase in the cellular levels of SRC members has been causally linked to the initiation and/or progression of a number of clinical disorders. Although knockout mouse models have underscored the critical non-redundant roles for each SRC member in vivo, there are surprisingly few mouse models that have been engineered to overexpress SRCs. This deficiency is significant since SRC involvement in many of these disorders is based on unscheduled increases in the levels (rather than the absence) of SRC expression. To address this deficiency, we used recent mouse technology that allows for the targeted expression of human SRC-2 in cells which express the progesterone receptor. Through cre-loxP recombination driven by the endogenous progesterone receptor promoter, a marked elevation in expression levels of human SRC-2 was achieved in endometrial cells that are positive for the progesterone receptor. As a result of this increase in coregulator expression, female mice are severely subfertile due to a dysfunctional uterus, which exhibits a hypersensitivity to estrogen exposure. Our findings strongly support the proposal from clinical observations that increased levels of SRC-2 are causal for a number of endometrial disorders which compromise fertility. Future studies will use this mouse model to decipher the molecular mechanisms that underpin the endometrial defect. We believe such mechanistic insight may provide new molecular descriptors for diagnosis, prognosis, and/or therapy in the clinical management of female infertility.

Show MeSH
Related in: MedlinePlus