RA-RAR signaling promotes mouse vaginal opening through increasing β-catenin expression and vaginal epithelial cell apoptosis.
RA-RAR signaling promotes mouse vaginal opening through increasing β-catenin expression and vaginal epithelial cell apoptosis.
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DOI：
10.1186/s12958-023-01084-8
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发表时间：
2023-04-11
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影响因子：
--
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视黄酸（RA）通过其受体（RARs）在胚胎苗勒管的维持和分化中起重要作用。然而，RA-RAR信号在阴道开口中的功能和机制尚不清楚。我们使用Rarα基因敲除小鼠模型和皮下注射RA（2.5 mg/kg）或E2（0.1 µg/kg）的野生型卵巢切除小鼠模型来研究RA-RAR信号在阴道开口中的作用和机制。采用实时荧光定量PCR和免疫荧光法检测Rarα基因缺失对Ctnnb 1 mRNA表达和细胞凋亡的影响。采用实时荧光定量PCR和Western blotting检测RA对阴道β-catenin表达和细胞凋亡的影响。采用实时荧光定量PCR和蛋白质印迹法分析E2对RA信号分子的影响。阴道上皮细胞表达RA信号分子，RALDH 2、RALDH 3、RARα和RARγ的mRNA和/或蛋白水平在阴道开放时达到高峰。Rarα基因缺失导致25.0%的女性阴道闭锁性不孕，其中阴道组织中Ctnnb 1、巴克和Bax的mRNA和蛋白表达水平显著降低，Bcl 2的mRNA表达水平显著升高。在阴道闭合的Rarα−/−雌性中，具有TUNEL和切割型Caspase-3阳性信号的阴道上皮百分比也显著降低。此外，RA补充卵巢切除的野生型（WT）女性显着增加β-catenin，活性β-catenin，巴克和BAX的表达，并显着降低BCL 2在阴道中的表达。因此，Rarα的缺失通过减少阴道β-catenin表达和上皮细胞凋亡来防止阴道开放。Rarα的缺失还导致血清雌二醇（E2）和阴道Raldh 2/3 mRNA水平显著降低。E2补充卵巢切除WT女性显着增加了阴道中RA信号分子的表达，表明阴道中RA信号分子的上调依赖于E2刺激。综上所述，我们认为阴道中的RA-RAR信号通过增加β-catenin表达和阴道上皮细胞凋亡来促进阴道开放。在线版本包含补充材料，可通过10.1186/s12958-023-01084-8获得。
Retinoic acid (RA) plays important role in the maintenance and differentiation of the Müllerian ducts during the embryonic stage via RA receptors (RARs). However, the function and mechanism of RA-RAR signaling in the vaginal opening are unknown. We used the Rarα knockout mouse model and the wild-type ovariectomized mouse models with subcutaneous injection of RA (2.5 mg/kg) or E2 (0.1 µg/kg) to study the role and mechanism of RA-RAR signaling on the vaginal opening. The effects of Rarα deletion on Ctnnb1 mRNA levels and cell apoptosis in the vaginas were analyzed by real-time PCR and immunofluorescence, respectively. The effects of RA on the expression of β-catenin and apoptosis in the vaginas were analyzed by real-time PCR and western blotting. The effects of E2 on RA signaling molecules were analyzed by real-time PCR and western blotting. RA signaling molecules were expressed in vaginal epithelial cells, and the mRNA and/or protein levels of RALDH2, RALDH3, RARα and RARγ reached a peak at the time of vaginal opening. The deletion of Rarα resulted in 25.0% of females infertility due to vaginal closure, in which the mRNA (Ctnnb1, Bak and Bax) and protein (Cleaved Caspase-3) levels were significantly decreased, and Bcl2 mRNA levels were significantly increased in the vaginas. The percentage of vaginal epithelium with TUNEL- and Cleaved Caspase-3-positive signals were also significantly decreased in Rarα−/− females with vaginal closure. Furthermore, RA supplementation of ovariectomized wild-type (WT) females significantly increased the expression of β-catenin, active β-catenin, BAK and BAX, and significantly decreased BCL2 expression in the vaginas. Thus, the deletion of Rarα prevents vaginal opening by reducing the vaginal β-catenin expression and epithelial cell apoptosis. The deletion of Rarα also resulted in significant decreases in serum estradiol (E2) and vagina Raldh2/3 mRNA levels. E2 supplementation of ovariectomized WT females significantly increased the expression of RA signaling molecules in the vaginas, suggesting that the up-regulation of RA signaling molecules in the vaginas is dependent on E2 stimulation. Taken together, we propose that RA-RAR signaling in the vaginas promotes vaginal opening through increasing β-catenin expression and vaginal epithelial cell apoptosis. The online version contains supplementary material available at 10.1186/s12958-023-01084-8.
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影响因子：
39.3
作者：
Liu J;Xiao Q;Xiao J;Niu C;Li Y;Zhang X;Zhou Z;Shu G;Yin G
通讯作者：
Yin G
影响因子：
3.3
作者：
Li, Rong;El Zowalaty, Ahmed E.;Chen, Weiqin;Dudley, Elizabeth A.;Ye, Xiaoqin
通讯作者：
Ye, Xiaoqin
影响因子：
5.5
作者：
Santana Gonzalez L;Rota IA;Artibani M;Morotti M;Hu Z;Wietek N;Alsaadi A;Albukhari A;Sauka-Spengler T;Ahmed AA
通讯作者：
Ahmed AA
DOI：
10.1073/pnas.90.15.7225
发表时间：
1993-08-01
影响因子：
11.1
作者：
LUFKIN, T;LOHNES, D;CHAMBON, P
通讯作者：
CHAMBON, P
影响因子：
16.6
作者：
Bowles J;Feng CW;Miles K;Ineson J;Spiller C;Koopman P
通讯作者：
Koopman P