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Gja1 Acts Downstream of Acvr1 to Regulate Uterine Decidualization Via Hand2 in Mice

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Gja1 Acts Downstream of Acvr1 to Regulate Uterine Decidualization Via Hand2 in Mice 233 2 H-F YU and others Gja1 regulation during 233:2 145–157 Research decidualization Gja1 acts downstream of Acvr1 to regulate uterine decidualization via Hand2 in mice Hai-Fan Yu, Zhan-Peng Yue, Kai Wang, Zhan-Qing Yang, Hong-Liang Zhang, Correspondence should be addressed Shuang Geng and Bin Guo to B Guo College of Veterinary Medicine, Jilin University, Changchun, People’s Republic of China Email [email protected] Abstract Although Gja1 has been proved to play an important role in uterine decidualization, its Key Words regulatory mechanism remains largely unknown. Here, we showed that Gja1 was highly f Gja1 expressed in the decidual cells and promoted the proliferation of uterine stromal cells f Acvr1 and expression of Prl8a2 and Prl3c1, which were two well-known differentiation markers f Hand2 for decidualization. Further analysis revealed that Gja1 might act downstream of Acvr1 f decidualization and cAMP to regulate the differentiation of uterine stromal cells. Administration of f uterine stromal cell cAMP analog 8-Br-cAMP to Acvr1 siRNA-transfected stromal cells resulted in an obvious Endocrinology increase of Gja1 expression, whereas PKA inhibitor H89 impeded the induction of of Gja1 elicited by Acvr1 overexpression, indicating that cAMP–PKA signal mediates the regulation of Acvr1 on Gja1 expression. In uterine stromal cells, knockdown of Gja1 Journal blocked the cAMP induction of Hand2. Moreover, siRNA-mediated downregulation of Hand2 impaired the stimulatory effects of Gja1 overexpression on the expression of Prl8a2 and Prl3c1, whereas constitutive expression of Hand2 reversed the inhibitory effects of Gja1 siRNA on stromal differentiation. Meanwhile, Gja1 might play a vital role in the crosstalk between Acvr1 and Hand2. Collectively, Gja1 may act downstream of cAMP–PKA signal to mediate the effects of Acvr1 on the differentiation of uterine Journal of Endocrinology stromal cells through targeting Hand2. (2017) 233, 145–157 Introduction Decidualization, a process where uterine stromal cells uterus exhibited decidualization failure in response to undergo extensive proliferation and differentiation an artificial stimulus (Clementi et al. 2013). Although into decidual cells, is essential for continued embryonic microarray analysis of oil-induced deciduoma in Acvr1- development and successful pregnancy (Dey et al. 2004, deficient mice has demonstrated that decidualization- Zhang et al. 2013). Inadequate decidualization causes related gene heart and neural crest derivatives expressed embryo miscarriage and early pregnancy loss irrespective transcript 2 (Hand2) was downregulated (Huyen & Bany of whether development of the blastocyst is normal 2011, Clementi et al. 2013), the underlying molecular (Kommagani et al. 2013). It has been previously reported mechanism of Acvr1 remains poorly understood. that activin A receptor type 1 (Acvr1, also referred to as Gap junctions, which are membranous channels for Alk2) played an important role in modulating uterine the exchange of small molecules directly between/among decidualization. Conditional ablation of Acvr1 in the adjacent cells or between cells and their extracellular http://joe.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-16-0583 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 02:12:12PM via free access 10.1530/JOE-16-0583 Research H-F YU and others Gja1 regulation during 233:2 146 decidualization environment, are critical for decidualization, because of vaginal plug). On days 1–4, pregnancy was confirmed its blockade could suppress the proliferation and by recovering embryos from the oviducts or uterus. The differentiation of uterine stromal cells (Yu et al. 2011, implantation sites on day 5 were identified by intravenous 2014a, Diao et al. 2013, Winterhager & Kidder 2015, injection of 0.1 mL of 1% Chicago blue (Sigma) in 0.85% Zappitelli et al. 2015). Gap junction protein alpha 1 (Gja1), sodium chloride. also known as connexin 43 (Cx43), was the principal and most well-studied component of the gap junctions. Loss of Gja1 expression in mouse uterus led to severe fertility Delayed implantation and activation defects due to the impaired stromal responsiveness To induce delayed implantation, pregnant mice were to implanting embryo and deciduogenic stimulus ovariectomized under ether anesthesia at 08:30–09:00 h accompanied with defective angiogenesis (Laws et al. on day 4 of pregnancy. Progesterone (1 mg/mouse; 2008). Similar results have been obtained in human Sigma) was injected subcutaneously to maintain delayed endometrial stromal cells in which attenuation of Gja1 implantation from days 5 to 7. Estradiol-17β (25 ng/ expression disrupted the gap junctional communication mouse, Sigma) was given to progesterone-primed delayed between neighboring cells and impeded the differentiation implantation mice to activate blastocyst implantation. of stromal cells (Laws et al. 2008, Yu et al. 2011). However, The mice were killed to collect uteri 24 h after estrogen there is still very limited information available regarding treatment. The implantation sites were identified by the regulatory mechanism of Gja1 in the process intravenous injection of Chicago blue solution. Delayed of decidualization. implantation was confirmed by flushing the blastocysts The present study was undertaken to examine from the uterus. the expression of Gja1 in mouse uterus during the pre-implantation period, explored its effects on the proliferation and differentiation of uterine stromal cells Artificial induced decidualization and focused on analyzing the interplay of Gja1, Acvr1, Artificial decidualization was induced by intraluminally Endocrinology cAMP and Hand2 in stromal differentiation. The results infusing 25 µL of sesame oil into one uterine horn on of showed that Gja1 was highly expressed in the decidual day 4 of pseudopregnancy, whereas the contralateral cells and induced the proliferation and differentiation uninjected horn served as a control. The mice were killed of uterine stromal cells. Furthermore, Gja1 might act Journal to collect uteri at 24, 48, 72 or 96 h after artificial-induced downstream of cAMP–PKA signal to mediate the effects decidualization. Decidualization was confirmed by of Acvr1 on the differentiation of uterine stromal cells by weighing the uterine horn and histological examination targeting Hand2. of uterine sections. Materials and methods In situ hybridization Animal Total RNAs from the mouse uteri were reverse-transcribed and amplified withGja1 primers. Gja1 forward primer Matured Kunming white strain mice (6–8 weeks old) 5′-GACTGCGGATCTCCAAAATA and reverse primer were caged in a controlled environment with a cycle of 5′-CTGTAATTCGCCCAGTTTTG were designed according 14L:10D. All animal procedures were approved by the to Mus musculus gap junction protein, alpha 1 (Gja1) gene Institutional Animal Care and Use Committee of Jilin (GenBank accession number NM_010288). The amplified University. To confirm reproducibility of results, at least fragment (167 bp) of Gja1 was cloned into pGEM-T three mice per group were used in each stage or treatment plasmid (pGEM-T Vector System 1; Promega) and verified in this study. by sequencing. Gja1-containing plasmid was amplified with the primers for T7 and SP6 to prepare templates for labeling. Digoxigenin (DIG)-labeled antisense and sense Pregnancy and pseudopregnancy cRNA probes were transcribed in vitro using a DIG RNA Adult female mice were mated with fertile or vasectomized labeling kit (Roche Diagnostics GmbH). males of the same strain to induce pregnancy or Frozen sections (10 µm) were mounted on pseudopregnancy by cocaging, respectively (day 1 = day 3-aminopropyltriethoxy silane (Sigma)-coated slides http://joe.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-16-0583 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 02:12:12PM via free access Research H-F YU and others Gja1 regulation during 233:2 147 decidualization and fixed in 4% paraformaldehyde solution in PBS. CFX96TM Real-Time Detection System. The conditions Hybridization was performed as described previously used for real-time PCR were as follows: 95°C for 3 min, (Tian et al. 2013). Sections were counterstained with 1% followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. methyl green. The positive signal was visualized as a dark Water was used to replace template cDNA for negative brown color. The sense probe was also hybridized and control. All reactions were run in triplicate. The result served as a negative control. There was no detectable was analyzed using CFX Manager Software. After analysis signal from sense probes. using the 2−ΔΔCt method, data were normalized to Gapdh expression. Primer sequences for real-time PCR were listed in Table 1. Specificities of all primers were confirmed Real-time PCR based on the agarose gel electrophoresis, sequencing and Total RNAs from mouse uteri or cultured cells were melting curves analysis. isolated using TRIPURE reagent (Roche) according to the manufacturer’s instructions, digested with RQ1 deoxyribonuclease I (Promega) to remove genomic DNA Isolation of uterine stromal cells and reverse-transcribed into cDNA with M-MLV reverse Uterine stromal cells from day 4 of pregnancy were transcriptase (Promega). Reverse transcription was isolated by enzymatic digestion as previously described performed at 42°C for 60 min with 2 µg total RNA in 25 µL (Tian
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