Ptn functions downstream of C/EBPβ to mediate the effects of cAMP on uterine stromal cell differentiation through targeting Hand2 in response to progesterone

Yu, Hai-Fan; Tao, Ran; Yang, Zhan-Qing; Wang, Kai; Yue, Zhan‐Peng; Guo, Bin

doi:10.1002/jcp.26067

Cited by 18 publications

(35 citation statements)

References 33 publications

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“…It has previously been reported that progesterone was essential for the differentiation of uterine stromal cells during decidualization [2, 27, 28]. As described above, progesterone could promote the expression of Hmgn2 which played an important role in stromal differentiation.…”

Section: Resultsmentioning

confidence: 82%

“…Collectively, these results reveal that Hmgn2 is a critical downstream target of progesterone in regulating stromal differentiation during decidualization. Previous studies have found that progesterone induced the accumulation of Hand2 mRNA in uterine stromal cells [28, 31]. However, once transfection with Hmgn2 siRNA, the induction of Hand2 by progesterone was abolished, implying that Hmgn2 is required in the crosstalk between progesterone and Hand2.…”

Section: Discussionmentioning

confidence: 87%

“…8C). Previous evidence had displayed that Hand2 was a well-characterized progesterone-responsive gene [28, 31]. We next dissected the role of Hmgn2 in progesterone regulation of Hand2.…”

Section: Resultsmentioning

confidence: 99%

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Evidence For Hmgn2 Involvement in Mouse Embryo Implantation and Decidualization

Yue

Yang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Hmgn2 is involved in regulating embryonic development, but its physiological function during embryo implantation and decidualization remains unknown. Methods: In situ hybridization, real-time PCR, RNA interference, gene overexpression and MTS assay were used to examine the expression of Hmgn2 in mouse uterus during the pre-implantation period and explore its function and regulatory mechanisms in epithelial adhesion junction and stromal cell proliferation and differentiation. Results: Hmgn2 was primarily accumulated in uterine luminal epithelia on day 4 of pregnancy and subluminal stromal cells around the implanting blastocyst at implantation sites on day 5. Similar results were observed during delayed implantation and activation. Meanwhile, Hmgn2 expression was visualized in the decidua. In uterine epithelial cells, silencing of Hmgn2 by specific siRNA reduced the expression of adhesion molecules Cdh1, Cdh2 and Ctnnb1 and enhanced the expression of Muc1, whereas constitutive activation of Hmgn2 exhibited the opposite effects, suggesting a role for Hmgn2 in attachment reaction during embryo implantation. Estrogen stimulated the expression of Hmgn2 in uterine epithelia, but the stimulation was abrogated by ER antagonist ICI 182,780. Further analysis evidenced that attenuation of Hmgn2 might eliminate the regulation of estrogen on the expression of Cdh1, Cdh2 and Ctnnb1. In uterine stromal cells, progesterone induced the accumulation of Hmgn2 which advanced the expression of Prl8a2 and Prl3c1, two well-known differentiation markers for decidualization, but did not affect the proliferation of stromal cells. Knockdown of Hmgn2 blocked the progesterone-induced differentiation of uterine stromal cells. Moreover, Hmgn2 might serve as an intermediate to mediate the regulation of progesterone on Hand2. Conclusion: Hmgn2 may play an important role during embryo implantation and decidualization.

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Section: Resultsmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 87%

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Evidence For Hmgn2 Involvement in Mouse Embryo Implantation and Decidualization

Yue

Yang

et al. 2017

Cell Physiol Biochem

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“…Primer sequences were shown as follows: 5′-CCCGGATGCTTCTGTCAACT and 5′-AACGAGCCTTGTCAGCCTTT (Hmgb1); 5′-CACCGGATCTAGACATGCCC and 5′-ACGTCTGTGGAACAGCAGAG (Klf5); 5′-CGCAGCTTCCATCACGAA and 5′-CACTGGGGACAGAACTTAAA (Bmp2). The other primer sequences used in this study were described previously [16].…”

Section: Real-time Pcrmentioning

confidence: 99%

“…Hybridization was performed as described previously [16]. Sections were counterstained with 1% methyl green.…”

Section: In Situ Hybridizationmentioning

confidence: 99%

High Mobility Group Box 1 Regulates Uterine Decidualization through Bone Morphogenetic Protein 2 and Plays a Role in Kruppel-Like Factor 5-Induced Stromal Differentiation

Wang

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: High mobility group box 1 (Hmgb1) is associated with a variety of physiological processes including embryonic development, cell proliferation and differentiation, but little information is available regarding its biological role in decidualization. Methods: In situ hybridization, real-time PCR, RNA interference, gene overexpression and MTS assay were used to analyze the spatiotemporal expression of Hmgb1 in mouse uterus during the pre-implantation period, and explore its function and regulatory mechanisms during uterine decidualization. Results: Hmgb1 mRNA was obviously observed in uterine epithelium on day 2 and 3 of pregnancy, but its expression was scarcely detected on day 4 of pregnancy. With the onset of embryo implantation, abundant Hmgb1 expression was noted in the subluminal stromal cells around the implanting blastocyst at implantation sites. Meanwhile, the accumulation of Hmgb1 mRNA was visualized in the decidual cells. Hmgb1 advanced the proliferation of uterine stromal cells and induced the expression of prolactin family 8, subfamily a, member 2 (Prl8a2), a reliable differentiation marker for decidualization. In uterine stromal cells, cAMP analogue 8-Br-cAMP up-regulated the expression of Hmgb1, but the up-regulation was abrogated by protein kinase A (PKA) inhibitor H89. Silencing of Hmgb1 by specific siRNA impeded the induction of 8-Br-cAMP on Prl8a2. Further analysis evidenced that Hmgb1 was a critical mediator of Kruppel-like factor 5 (Klf5) function in stromal differentiation. Knockdown of bone morphogenetic protein 2 (Bmp2) prevented the up-regulation of Prl8a2 elicited by Hmgb1 overexpression, whereas addition of exogenous recombinant Bmp2 protein (rBmp2) reversed the repression of Hmgb1 siRNA on Prl8a2 expression. Conclusion: Hmgb1 may play an important role during mouse uterine decidualization.

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Egr3 as an important regulator of uterine decidualization through targeting Hand2

Yue

Tian

et al. 2022

Cell Biology International

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Early growth response 3 (Egr3) is required for embryogenesis, but little understanding is usable about its function in embryo implantation and decidualization. The present study exhibited an obvious localization of Egr3 in luminal epithelium and subluminal stroma at implantation sites. Administration of estrogen brought about a distinct gather of Egr3 mRNA in uterine luminal and glandular epithelia. Meanwhile, Egr3 was visualized in the decidua where it might facilitate the proliferation of stromal cells via Ccnd3 and accelerate stromal differentiation, testifying the significance of Egr3 in decidualization. In ovariectomized mice uteri or stromal cells, progesterone advanced the expression of Egr3 whose obstruction counteracted the inducement of stromal differentiation by progesterone. Consistently, Egr3 mediated the influence of cAMP and heparin‐binding EGF‐like growth factor (HB‐EGF) on the differentiation program. Additionally, cAMP‐protein kinase A (PKA) signaling mediated the adjustment of progesterone on Egr3. Impediment of HB‐EGF antagonized the ascendance of Egr3 conferred by cAMP. In stromal cells, Egr3 activated the transcription of Hand2 whose promoter region exhibited the binding enrichment of Egr3. Activation of Hand2 relieved the weakness of stromal differentiation by Egr3 hinderance, whereas knockdown of Hand2 neutralized the guidance of Egr3 overexpression on the differentiation program. Collectively, Egr3 was identified as an important regulator of uterine decidualization through targeting Hand2 in response to progesterone/cAMP/HB‐EGF pathway.

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Ptn functions downstream of C/EBPβ to mediate the effects of cAMP on uterine stromal cell differentiation through targeting Hand2 in response to progesterone

Cited by 18 publications

References 33 publications

Evidence For Hmgn2 Involvement in Mouse Embryo Implantation and Decidualization

Evidence For Hmgn2 Involvement in Mouse Embryo Implantation and Decidualization

High Mobility Group Box 1 Regulates Uterine Decidualization through Bone Morphogenetic Protein 2 and Plays a Role in Kruppel-Like Factor 5-Induced Stromal Differentiation

Egr3 as an important regulator of uterine decidualization through targeting Hand2

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