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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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The SRC-2:OE mouse exhibits a severe subfertility defect.(A) A six-month breeding study reveals that the SRC-2:OE female mouse is severely subfertile. (B) SRC-2LSL and SRC-2:OE mice produce similar numbers of oocytes following sequential PMSG and hCG hormone treatments (see: Materials and Methods). (C) Similar levels of E2 and P4 are found in the serum of the SRC-2LSL and SRC-2:OE mouse.
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pone-0098664-g005: The SRC-2:OE mouse exhibits a severe subfertility defect.(A) A six-month breeding study reveals that the SRC-2:OE female mouse is severely subfertile. (B) SRC-2LSL and SRC-2:OE mice produce similar numbers of oocytes following sequential PMSG and hCG hormone treatments (see: Materials and Methods). (C) Similar levels of E2 and P4 are found in the serum of the SRC-2LSL and SRC-2:OE mouse.

Mentions: A six month breeding program was employed to determine whether the SRC-2:OE shows a similar fecundity to its SRC-2LSL sibling. The SRC-2:OE mouse exhibits a significant decrease in fertility as evidenced by the small number of litters produced by the SRC-2:OE group when compared to the SRC-2LSL group (Fig. 5A). Specifically, four out of nine SRC-2:OE mice failed to produce litters. From the remaining five SRC-2:OE mice, three mice produced one litter whereas the other two females yielded three litters; however, these litters on average were smaller when compared to the control group (average 6.5 pups/litter in the SRC-2LSL group vs. 3.2 pups/litter in the SRC-2:OE group). To assess whether the basis of the subfertility defect is linked (in whole or in part) with ovarian dysfunction, an established gonadotropin hormone regimen was used to elicit superovulation in juvenile SRC-2:OE and SRC-2LSL mice (Fig. 5B; Material and Methods [40]). The results in Fig. 5B clearly shows that ovarian function in the SRC-2:OE is not compromised; this conclusion is further supported by equivalent serum levels of E2 and P4 in the SRC-2:OE and SRC-2LSL mouse groups (Fig. 5C). Collectively, these data reveal a significant subfertility defect is linked to high levels of human SRC-2 expression in the SRC-2:OE; however, the basis of this reproductive phenotype is not due to an anovulatory phenotype.


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)

The SRC-2:OE mouse exhibits a severe subfertility defect.(A) A six-month breeding study reveals that the SRC-2:OE female mouse is severely subfertile. (B) SRC-2LSL and SRC-2:OE mice produce similar numbers of oocytes following sequential PMSG and hCG hormone treatments (see: Materials and Methods). (C) Similar levels of E2 and P4 are found in the serum of the SRC-2LSL and SRC-2:OE mouse.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098664-g005: The SRC-2:OE mouse exhibits a severe subfertility defect.(A) A six-month breeding study reveals that the SRC-2:OE female mouse is severely subfertile. (B) SRC-2LSL and SRC-2:OE mice produce similar numbers of oocytes following sequential PMSG and hCG hormone treatments (see: Materials and Methods). (C) Similar levels of E2 and P4 are found in the serum of the SRC-2LSL and SRC-2:OE mouse.
Mentions: A six month breeding program was employed to determine whether the SRC-2:OE shows a similar fecundity to its SRC-2LSL sibling. The SRC-2:OE mouse exhibits a significant decrease in fertility as evidenced by the small number of litters produced by the SRC-2:OE group when compared to the SRC-2LSL group (Fig. 5A). Specifically, four out of nine SRC-2:OE mice failed to produce litters. From the remaining five SRC-2:OE mice, three mice produced one litter whereas the other two females yielded three litters; however, these litters on average were smaller when compared to the control group (average 6.5 pups/litter in the SRC-2LSL group vs. 3.2 pups/litter in the SRC-2:OE group). To assess whether the basis of the subfertility defect is linked (in whole or in part) with ovarian dysfunction, an established gonadotropin hormone regimen was used to elicit superovulation in juvenile SRC-2:OE and SRC-2LSL mice (Fig. 5B; Material and Methods [40]). The results in Fig. 5B clearly shows that ovarian function in the SRC-2:OE is not compromised; this conclusion is further supported by equivalent serum levels of E2 and P4 in the SRC-2:OE and SRC-2LSL mouse groups (Fig. 5C). Collectively, these data reveal a significant subfertility defect is linked to high levels of human SRC-2 expression in the SRC-2:OE; however, the basis of this reproductive phenotype is not due to an anovulatory phenotype.

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