Limits...
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.

Show MeSH

Related in: MedlinePlus

Cellular and molecular analysis of the endometrial decidualization defect in the SRC-2:OE mouse.(A) Top panels show low magnification images of transverse sections of the stimulated (S) uterine horn immunostained for phospho-histone H3 from the SRC-2LSL and SRC-2:OE mouse. Bottom panels are higher magnification images of tissue areas denoted by a box shown in the corresponding top panels. Black arrowhead in bottom left panel indicates a decidual cell; white arrowhead points to a mitotic figure. Black arrowhead in bottom right panel indicates luminal epithelial cells positive for phospho-histone H3 whereas the white arrowhead shows a stromal cell immuno-positive for phospho-histone H3. Note the intact luminal epithelium (LE); S denotes stroma. Scale bar in top and bottom left panels apply to corresponding right panels. (B) Real time PCR analysis of Bmp2 (Bone morphogenetic protein 2), Fst (Follistatin), Hand2 (Heart and neural crest derivatives expressed transcript 2), and Wnt4 (Wingless-related MMTV integration site 4) transcript levels in the control and stimulated uterine horns of SRC-2LSL and SRC-2:OE mice.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4048228&req=5

pone-0098664-g007: Cellular and molecular analysis of the endometrial decidualization defect in the SRC-2:OE mouse.(A) Top panels show low magnification images of transverse sections of the stimulated (S) uterine horn immunostained for phospho-histone H3 from the SRC-2LSL and SRC-2:OE mouse. Bottom panels are higher magnification images of tissue areas denoted by a box shown in the corresponding top panels. Black arrowhead in bottom left panel indicates a decidual cell; white arrowhead points to a mitotic figure. Black arrowhead in bottom right panel indicates luminal epithelial cells positive for phospho-histone H3 whereas the white arrowhead shows a stromal cell immuno-positive for phospho-histone H3. Note the intact luminal epithelium (LE); S denotes stroma. Scale bar in top and bottom left panels apply to corresponding right panels. (B) Real time PCR analysis of Bmp2 (Bone morphogenetic protein 2), Fst (Follistatin), Hand2 (Heart and neural crest derivatives expressed transcript 2), and Wnt4 (Wingless-related MMTV integration site 4) transcript levels in the control and stimulated uterine horns of SRC-2LSL and SRC-2:OE mice.

Mentions: Comparative histological analysis of the mid-section of the SRC-2LSL and SRC-2:OE stimulated uterine horns clearly underscores the SRC-2:OE decidual defect at the cellular level (Fig. 7A). Apart from the striking difference in the size of the respective uterine horns, the SRC-2LSL stromal compartment contains numerous large decidual cells interspersed with a small number of proliferating stromal cells (at this stage of decidualization, the luminal epithelium is absent [55]). In contrast, decidual cells are not detected in the SRC-2:OE stromal compartment (Fig. 7A). Strikingly, the luminal epithelial compartment remains intact in the SRC-2:OE endometrium, with a subset of epithelial cells still undergoing active proliferation (Fig. 7A). Given the severity of the decidual phenotype, its not surprising that many changes of gene expression previously associated with endometrial decidualization and critical for normal endometrial function are not induced in the stimulated uterine horn of the SRC-2:OE mouse (Fig. 7B, Fig. S5). Therefore, our results show that a breakdown in the endometrial decidual progression program underpins the subfertility defect displayed by the SRC-2:OE mouse. Future investigations will determine whether embryo attachment to the apical surface of the luminal epithelium (which triggers decidualization in the subepithelial stroma) or a progression step later in the decidual program accounts for the decidualization impairment observed in SRC-2:OE uterus.


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)

Cellular and molecular analysis of the endometrial decidualization defect in the SRC-2:OE mouse.(A) Top panels show low magnification images of transverse sections of the stimulated (S) uterine horn immunostained for phospho-histone H3 from the SRC-2LSL and SRC-2:OE mouse. Bottom panels are higher magnification images of tissue areas denoted by a box shown in the corresponding top panels. Black arrowhead in bottom left panel indicates a decidual cell; white arrowhead points to a mitotic figure. Black arrowhead in bottom right panel indicates luminal epithelial cells positive for phospho-histone H3 whereas the white arrowhead shows a stromal cell immuno-positive for phospho-histone H3. Note the intact luminal epithelium (LE); S denotes stroma. Scale bar in top and bottom left panels apply to corresponding right panels. (B) Real time PCR analysis of Bmp2 (Bone morphogenetic protein 2), Fst (Follistatin), Hand2 (Heart and neural crest derivatives expressed transcript 2), and Wnt4 (Wingless-related MMTV integration site 4) transcript levels in the control and stimulated uterine horns of SRC-2LSL and SRC-2:OE mice.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098664-g007: Cellular and molecular analysis of the endometrial decidualization defect in the SRC-2:OE mouse.(A) Top panels show low magnification images of transverse sections of the stimulated (S) uterine horn immunostained for phospho-histone H3 from the SRC-2LSL and SRC-2:OE mouse. Bottom panels are higher magnification images of tissue areas denoted by a box shown in the corresponding top panels. Black arrowhead in bottom left panel indicates a decidual cell; white arrowhead points to a mitotic figure. Black arrowhead in bottom right panel indicates luminal epithelial cells positive for phospho-histone H3 whereas the white arrowhead shows a stromal cell immuno-positive for phospho-histone H3. Note the intact luminal epithelium (LE); S denotes stroma. Scale bar in top and bottom left panels apply to corresponding right panels. (B) Real time PCR analysis of Bmp2 (Bone morphogenetic protein 2), Fst (Follistatin), Hand2 (Heart and neural crest derivatives expressed transcript 2), and Wnt4 (Wingless-related MMTV integration site 4) transcript levels in the control and stimulated uterine horns of SRC-2LSL and SRC-2:OE mice.
Mentions: Comparative histological analysis of the mid-section of the SRC-2LSL and SRC-2:OE stimulated uterine horns clearly underscores the SRC-2:OE decidual defect at the cellular level (Fig. 7A). Apart from the striking difference in the size of the respective uterine horns, the SRC-2LSL stromal compartment contains numerous large decidual cells interspersed with a small number of proliferating stromal cells (at this stage of decidualization, the luminal epithelium is absent [55]). In contrast, decidual cells are not detected in the SRC-2:OE stromal compartment (Fig. 7A). Strikingly, the luminal epithelial compartment remains intact in the SRC-2:OE endometrium, with a subset of epithelial cells still undergoing active proliferation (Fig. 7A). Given the severity of the decidual phenotype, its not surprising that many changes of gene expression previously associated with endometrial decidualization and critical for normal endometrial function are not induced in the stimulated uterine horn of the SRC-2:OE mouse (Fig. 7B, Fig. S5). Therefore, our results show that a breakdown in the endometrial decidual progression program underpins the subfertility defect displayed by the SRC-2:OE mouse. Future investigations will determine whether embryo attachment to the apical surface of the luminal epithelium (which triggers decidualization in the subepithelial stroma) or a progression step later in the decidual program accounts for the decidualization impairment observed in SRC-2:OE uterus.

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