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International Journal of Clinical and Experimental Pathology logoLink to International Journal of Clinical and Experimental Pathology
. 2018 May 1;11(5):2514–2521.

Activation of β-catenin causes defects in embryonic development during maternal-to-zygotic transition in mice

Jun Yu 1,2,*, Xueke Guo 1,*, Xia Chen 1,*, Chen Qiao 3,*, Binghai Chen 4,*, Bing Xie 1,5, Xiaojin Luan 1, Cong Shen 6, Jiawei Zhu 6, Jiajia Liu 1, Yidan Yan 1, Zeyu He 7, Bo Zheng 6, Hong Li 6, Jie Fang 1
PMCID: PMC6958268  PMID: 31938364

Abstract

The early stage of embryogenesis is an important and complex cell-remodeling event in reproductive biology. To develop into a normal zygote, maternal-to-zygotic transition (MZT) is especially important for both zygotic genome activation (ZGA) and degradation of maternal products during the early stage of embryonic development. β-Catenin has been identified as an important regulator of embryonic development and adult stem cell division via the canonical Wnt/β-catenin signalling pathway. However, the role of activated β-catenin during MZT remains elusive. In the present study, we found that β-catenin is mainly expressed during embryogenesis in the cell membrane from the zygote- to morula-stage embryos but not in MII oocytes. To analyze the function of activated β-catenin during MZT, we conducted a β-catenin activation assay during embryogenesis. Our results indicated that development beyond the two-cell stage was inhibited in zygotes with β-catenin activation. Further analysis showed that activated form of β-catenin protein was increased and the phosphorylated form of β-catenin protein was decreased in culture embryos. Taken together, our study reveals that activation of β-catenin may play a vital role in zygotic development, determining the developmental potential of mouse embryos.

Keywords: β-catenin, embryonic development, maternal-to-zygotic transition, SKL2001, two-cell stage block

Introduction

The early stage of embryogenesis is an important and complex cell-remodelling event in reproductive biology [1]. Fertilized eggs are strictly controlled by maternal factors that are accumulated and stored in the mature oocytes [2,3]. To develop into a normal zygote, maternal-to-zygotic transition (MZT) is especially important for both zygotic genome activation (ZGA) and degradation of maternal products during the early stage of embryonic development [1,4]. Maternal mRNAs and proteins, synthesized and stored during oocyte growth, are required for the maternal contribution and to maintain the development of early embryos, while the zygotic genome is asynchronously activated in embryonic development [3-5].

To eliminate the contribution of maternal factors, maternally supplied mRNAs must be degraded in the early embryonic stages. A previous study on Drosophila demonstrated that the 3’-untranslated region (UTR) of maternal transcripts mediates the degradation of maternal products [6]. After MZT, the zygotic genome needs to be activated and controls embryonic development. A report showed that the zinc-finger protein Zelda is a key activator of the early zygotic genome in Drosophila [7]. In mammals, the yes-associated protein (YAP) is highly expressed in oocytes and early embryos [8,9]. A previous study demonstrated that maternal YAP serves as a significant activator of the early zygotic genome in mice. Yap1-knockout embryos exhibit a prolonged two-cell stage and develop into the four-cell stage at a much slower pace compared to their wild-type counterparts. The maternal YAP protein targets ribosomal protein L13 (Rpl13) and ribonucleotide reductase M2 (Rrm2) to affect preimplantation embryos [10,11]. More importantly, a recent study found that B-cell translocation gene-4 (BTG4) is an MZT licensing factor in mice, and knockout of the Btg4 gene caused fertility defects although the oocytes of Btg4-knockout mice appeared morphologically normal. This may be caused by early developmental arrest. Further results indicated that the BTG4 protein can bridge CCR4-NOT transcription complex subunit 7 (CNOT7), which is a catalytic protein for CCR4-NOT deadenylase, to eukaryotic translation initiation factor 4E (eIF4E), and facilitate the decay of maternal mRNA [12].

For developing into a totipotent embryo, many pathways with cross-talk signals are involved in the early stages of embryonic development. These pathways control the normal division of blastomeres, and help neighbouring cells work together to form specialized structures. Previous studies have shown the significant role of Wnt/β-catenin signalling for gastrulation [13-15]. Wnt signalling has been shown to destroy the stability of the GSK-3β/CK1α/AXIN2/APC complex and inhibit the degradation of cytosolic β-catenin [16,17].

β-Catenin, also known as Ctnnb1, encodes a protein containing armadillo repeat domain. It can be stabilized by adenomatous polyposis coli (APC) and participates in adherens junctions [18]. A previous study showed that β-catenin plays basic roles in establishing epithelial polarity in all metazoans [19,20]. Stabilized β-catenin can translocate to the nucleus, where it binds with TCF transcription factors and downstream genes [16,17]. In humans, β-catenin and Wnt signalling-dependent proteins are expressed mainly in the uterine stroma and plasma membranes of the villous cytotrophoblasts and glandular epithelium [21-23]. Downregulation of the Wnt/β-catenin signalling pathway might be associated with the pathogenesis of recurrent spontaneous abortion [21]. In a previous study in pregnant women, Fan et al. showed that β-catenin, mediated by RAS-related C3 botulinum substrate 1 (RAC1), might regulate Snail and matrix metallopeptidase 9 (MMP9) protein expression, subsequently promoting trophoblast invasion in pregnant women [24]. β-Catenin and Snail are the key factors required for cell polarity and invasion [25,26]. Moreover, the nuclear accumulation of β-catenin influences growth- and invasion-related genes, including c-myc and matrix metallopeptidase 7 (MMP7) [27,28].

In mammals, β-catenin has already been known to play an important role in the Wnt/β-catenin signalling pathway, which triggers the earliest stages of embryo formation [17]. Mice lacking maternal/zygotic β-catenin do form preimplantation embryos, but the morphology and size are affected. Without the zona pellucida, maternal/zygotic β-catenin null embryos could form trophoblastic vesicles with retardation [29,30]. However, of the role played by activated β-catenin during MZT remains elusive. In the present study, we successfully generated an activated β-catenin assay during embryonic culture. We aimed to study the expression level and distribution of β-catenin in mouse oocytes and embryos and explore the effects of its ectopic expression in vitro.

Materials and methods

Mice

Mice with a C57BL/6J background were maintained under a controlled environment of 20-25°C in a 12/12-h light/dark cycle and 50-70% humidity, with free access to water and food. All animal procedures were approved by the Institutional Animal Care and Use Committee at Jiangsu University, and conducted according to the Guide for the Care and Use of Laboratory Animals.

Embryo collection and culture

Briefly, 6- to 8-week-old female C57BL/6J mice were superovulated by 10 IU human chorionic gonadotropin (hCG) injections followed by 10 IU of pregnant mare serum gonadotropin (PMSG) 48 h later. MII oocytes were collected from the ampullae of oviducts at 16 h after hCG injection. Zygotes were collected at 16 h post-hCG injection from the ampullae of oviducts of superovulated females that had been mated with C57BL/6J males. Cumulus cells were removed by digestion with hyaluronidase (Sigma) for several minutes. Embryos were cultured in fresh KSOM medium (Millipore) at 37°C in air containing 5% CO2. Two-cell-, four-cell-, morula-, and blastocyst-stage embryos were collected after 22-26, 48-50, 70-75 and 96-100 h of culture, respectively.

For the β-catenin activation assay, zygotes were collected at 16 h post-hCG and cultured in potassium simplex optimized medium (KSOM). The β-catenin activator (Selleck, SKL2001) was dissolved in dimethyl sulfoxide (DMSO) and diluted by KSOM to obtain a final concentration of 20 µM (Selleck, SKL2001). Embryos cultured in KSOM or KSOM with DMSO alone were used as the controls.

Immunofluorescence and antibodies

Embryos were treated with 1× phosphate-buffered saline (PBS) for 5 min at room temperature, and fixed for 30 min in 4% paraformaldehyde (PFA). After washing three times in 1×PBS with 0.1% Triton X-100 (PBST) and blocking for 1 h in 5% bovine serum albumin (BSA), the samples were incubated with primary antibodies overnight at 4°C. After washing three times for 10 min in 0.1% PBST, the samples were incubated for 1 h with secondary antibodies at room temperature, and washed three times in 0.1% PBST. Testes samples were stained with 1.0 mg/mL Hoechst-33342 (Invitrogen) for 5 min before mounting. Mouse monoclonal C-terminal β-catenin antibody (BD Transduction Laboratories; 1:100) was used as the primary antibodies. Secondary antibodies conjugated to A488-mouse or Cy3-mouse (Molecular Probes and Jackson Immunologicals) were used at a 1:1000 dilution.

Microinjection of small-interfering RNAs (siRNAs)

To knock down β-catenin, β-catenin siRNAs (siRNA-1, sense: 5’-CCAGGUGGUAGUUAAUAAATT-3’ and antisense: 5’-UUUAUUAACUACCACCUGGTT-3’; siRNA-2, sense: 5’-GGGUUCCGAUGAUAUAAAUTT-3’ and antisense: 5’-AUUUAUAUCAUCGGAACCCTT-3’) were purchased from GenePharma and diluted in buffer to 20 uM. Then, 5-10 pL of siRNA was microinjected into the cytoplasm of mouse zygotes in M2 medium (Sigma), and the zygotes were cultured in fresh KSOM medium. Non-silencing siRNA was used as the negative control. The zygotes were cultured for 24 h until they reached the two-cell stage, and collected to assess knockdown efficiency by real-time PCR.

Western blot analysis

Western blot analysis was performed according to the standard protocol with minor modifications. Briefly, proteins were separated by electrophoresis, and then transferred to polyvinylidene difluoride (PVDF) membranes (GE Healthcare). The membranes were then blocked in 5% non-fat milk and incubated overnight with the indicated primary antibodies, anti-β-catenin (D10A8), Cell Signaling Technology, 1:1000; anti-phospho-β-catenin, Cell Signaling Technology, 1:1000; anti-non-phospho-β-catenin (D2U8Y), Cell Signaling Technology, 1:1000; anti-tubulin, Beytime, 1:10000, washed, and incubated at room temperature for 1 h with horseradish peroxidase (HRP)-conjugated secondary antibodies (Thermo Scientific). Protein signals were then visualized by SuperSignal*West Femto Chemiluminescent Substrate (Thermo Scientific).

Quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR)

Total RNA was isolated from the embryos using an RNeasy Micro Kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol. Total RNA was converted to cDNA using Superscript reverse transcriptase and then amplified by Platinum Taq polymerase using the Superscript One Step qRT-PCR kit (Invitrogen). qRT-PCR was performed in a 25-μL reaction volume containing reaction buffer, Taq, 25 mM MgCl2, 2 mM dNTP, DEPC-H2O, cDNA, 100 pmol of specific primers, and SYBR Green I. The following primers were used, β-catenin: forward: 5’-ACTTGCCACACGTGCAATTC-3’ and reverse: 5’-ATGGTGCGTACAATGGCAGA-3’. GAPDH was used as internal control with the following primers: forward: 5’-TTGCAGTGGCAAAGTGGAGA-3’, and reverse: 5’-GATGGGCTTCCCGTTGATGA-3’. The relative changes in gene expression were calculated by the 2-ΔΔCt method.

Statistical analysis

Data were statistically evaluated by the Chi-square test or Student’s t test for differences between groups. Different levels of statistical significance were set: n.s. indicates no significance (P > 0.05); and P < 0.05, P < 0.01, and P < 0.001 were the different levels of statistical significance.

Results

β-Catenin expression pattern in oocytes and embryos

Previous studies have found that the Wnt/β-catenin signalling plays essential roles during early embryonic development in mice [31]. β-Catenin, which mediates cell-cell adhesion and recognition, has been shown to be related to cell adhesion and affects cadherin signalling activity [32]. To explore its role in mouse oocytes and embryos, we carried out immunofluorescence staining with antibodies to β-catenin to study its expression pattern. Our results showed that β-catenin is mainly distributed in the cell membrane of early embryos from zygotes to morulae. With progression of blastomere division, β-catenin is predominately expressed in the morula. However, β-catenin was not detected in the cell membrane of MII oocytes (Figure 1). Taken together, our data demonstrated that β-catenin is highly expressed in the cell membrane during early embryonic development.

Figure 1.

Figure 1

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β-Catenin expression pattern in oocytes and embryos. Immunofluorescence staining of MII oocytes; zygotes; and two-cell, four-cell, and morula-stage embryos. β-catenin was stained with anti-β-catenin (red), and DNA (blue) was stained with Hoechst-33342. Scale bars: 20 µm.

β-Catenin activation inhibits early embryonic development

During blastomere development seen in early embryogenesis, many signalling pathways help cells to communicate with each other. β-Catenin has already been shown to play key roles in the signalling pathways triggering the earliest stages of embryonic development. Previous studies have showed that zygotic loss of β-catenin did not affect preimplantation embryonic development [13,33]. To further examine the function of activated β-catenin in mouse embryos, we generated an activated β-catenin assay during embryo culture. Embryos cultured in KSOM and DMSO medium alone were used as the controls. The β-catenin activator (SKL2001) used here was a type of activator for activating the Wnt/β-catenin signalling pathway. We found that control embryos exhibited normal development beyond the two-cell stage and into the four-cell stage and subsequently formed morula. Interestingly, almost all activated β-catenin embryos (SKL2001) could not go beyond the two-cell stage (Figure 2).

Figure 2.

Figure 2

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Effect of activated β-catenin during early embryonic development. Representative images captured by light microscopy show early embryonic development defects. The control embryos (treated with KSOM and DMSO) could normally develop beyond two-cell stage, while the activated β-catenin embryos (treated with SKL2001) developed arrest at the two-cell stage. Scale bar: 100 µm.

Activation of β-catenin affects the rate of blastocyst formation

To further analyze the effects of β-catenin on embryonic development, we calculated the rate of embryo formation at each stage (Figure 3). Both the control and activated β-catenin embryos could develop into the two-cell stage (KSOM control, 97.67% of zygotes developed into two-cell stage embryos, n = 129; DMSO, 95.12% of zygotes developed into two-cell stage embryos, n = 123; activated β-catenin, 93.10% of zygotes developed into two-cell stage embryos, n = 116), and there was no significant difference (n.s.) in the formation rates among the three groups. The control embryos further developed into four-cell- (KSOM, 93.80%; DMSO, 89.43%), morula- (KSOM, 89.15%; DMSO, 86.99%) and blastula (KSOM, 84.50%; DMSO, 85.37%) -stage embryos, while only few activated β-catenin embryos could develop into the four-cell (6.03%) and morula (1.72%) stages, and no blastulas (0.00%) were formed. In summary, our study suggested the key roles of β-catenin activation signals in early embryonic development.

Figure 3.

Figure 3

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Formation rate of early embryos. Analysis of the formation rate of embryos from zygote to blastula. Activation of β-catenin affects early embryonic development. Data were evaluated by the Chi-square test to determine statistically significant differences between groups. n.s. = P > 0.05, ***P < 0.001. Error bars represent SD.

SKL2001 induces β-catenin signaling

To confirm activation of β-catenin, we detected its expression level in culture embryos. The results of the Western blot analysis showed that the expression of β-catenin was significantly increased in β-catenin-activated embryos at the two-cell stage compared with the controls. Moreover, further analysis showed that the activated form of β-catenin protein was increased, while the phosphorylated form of β-catenin protein was significantly decreased (Figure 4). Taken together, our results indicate that β-catenin is indeed activated and induced Wnt/β-catenin signaling in the test embryos.

Figure 4.

Figure 4

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SKL2001 induces β-catenin activation. Western blot analysis of total β-catenin protein, phosphorylated form of β-catenin protein and activated form of β-catenin protein level in KSOM, DMSO, and SKL2001 treated embryos at the two-cell stage.

Knockdown of β-catenin does not affect the early stage of embryonic development

The significant role of Wnt/β-catenin signalling in gastrulation has been previously demonstrated, and it was found that preimplantation embryos can be formed at an early stage in β-catenin knockout mice [13,15]. To further analyse the loss of function of β-catenin during MZT in vitro, we injected cultured zygotes with β-catenin siRNAs. qRT-PCR results showed that knockdown of β-catenin by siRNAs in culture embryos at two-cell stage reduced the expression of β-catenin mRNA (Figure 5A).

Figure 5.

Figure 5

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Effects of β-catenin knockdown on early embryonic development. A: qRT-PCR analysis shows high knockdown efficiency of β-catenin by siRNA. B: Formation rate of early embryos microinjected with NC and siRNAs. Knockdown efficiency data were evaluated by the student’s t test, and the early embryo formation rate was analysed by the Chi-square test to detect statistically significant differences between groups. n.s. P > 0.05, *P < 0.05, **P < 0.01. Error bars represent SD.

Although siRNAs down-regulated the β-catenin mRNA expression, zygotes injected with exogenous β-catenin siRNA did not show arrest at the two-cell stage (two-cell stage: 95.24% embryos with siRNA-1, n = 63, and 95.65% embryos with siRNA-2, n = 69; four-cell stage: 90.48% embryos with siRNA-1 and 91.30% embryos with siRNA-2) and can develop into the blastula stage (siRNA-1, 76.19%; siRNA-2, 76.81%) compared to the KSOM control embryos (two-cell-stage embryos, 94.67%; blastula, 82.67%; n = 75) (Figure 5B). Our data suggest that embryos lacking β-catenin develop beyond the two-cell stage with no obvious developmental defects during MZT.

Discussion

In this study, we identified β-catenin as an MZT factor that was vital for embryonic development during MZT in mice, and we found high β-catenin expression levels in the cytoplasmic membrane of early embryos from zygotes to morulae, but not in the MII oocytes. Furthermore, we generated an activated β-catenin assay in an embryonic culture system. Our data suggest that embryos with aberrant activation of β-catenin do not develop beyond the two-cell stage and exhibit developmental arrest. Overall, our results demonstrate that β-catenin might regulate embryo development by influencing the Wnt/β-catenin pathway during MZT.

Currently, there is no consensus about loss of function of β-catenin in mouse embryos. Some studies have shown that zygotic deficiency of β-catenin does not affect preimplantation development [13,15,33]. In contrast, some reports claim that β-catenin is required for implantation and normal morphology of early-stage embryos [30,34], and zygotic β-catenin knockout mutants were not efficient. Our study showed that knockdown of β-catenin in cultured embryos did not affect the early stage of embryonic development. This may be due to maternal contribution and the compensation effect of E-cadherin [29].

During the MZT, maternal proteins in oocytes are degraded by the ubiquitin-proteasome system (UPS), and new proteins are synthesized from the zygotic genome [35]. The mRNAs stored in oocytes undergo general decay during MZT, and their stability is tightly interconnected with meiotic cell cycle progression. To begin the process of transcription of zygotic genes, embryos must first overcome the established silencing of their genes. More recently, evidence illustrates that transcription of a subset of genes in Drosophila is delayed by one cell cycle in haploid embryos [36]. Previous research has shown that p120 catenin (p120ctn) was required to stabilize and regulate cadherin-mediated cell-cell adhesion, and p120ctn deficiency in mouse embryonic stem cells influenced the formation of cystic embryoid bodies and caused defects in primitive endoderm formation [37].

However, specific mechanisms of embryonic development during MZT are not yet well understood. Our study suggests that β-catenin activates Wnt/β-catenin pathway and plays key roles in embryonic development during MZT, which determines the developmental potential of embryos. To pinpoint the underlying mechanism of β-catenin, further studies are needed to focus on the activation of zygotic genes affected by Wnt/β-catenin pathway.

Acknowledgements

We would like to thank the native English speaking scientists of Elixigen Company (Huntington Beach, California) for editing our manuscript. This work was supported by Key Research Foundation of Zhenjiang Social Development (SH2016028, SH2017013, SH2017020, SH2016031, SH2014026), Key Research Foundation of Zhenjiang Health Science and Technology (SHW2016001), Science Foundation of Doctorate Research of the Affiliated Hospital of Jiangsu University (jdfyRC2016005), Suzhou Key Medical Center (SZZX201505), Suzhou Introduced Project of Clinical Medical Expert Team (SZYJTD201708) and Jiangsu Provincial Medical Innovation Team (CXTDB2017013). National Natural Science Foundation of China (81402100), the Foundation of Health and Family Planning Commission of Jiangsu Province (Q201408), the Foundation for Young Medical Talents of Jiangsu province (QNRC2016840), Six Talent Peaks Project in Jiangsu Province (WSW-007). This article does not contain any studies with informed consent by any of the authors.

Disclosure of conflict of interest

None.

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