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Xiaotong Wu X Wu, college of animal sciences, Zhejiang University, Hangzhou, China

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Yan Shi Y Shi, college of animal sciences, Zhejiang University, Hangzhou, China

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Bingjie Hu B Hu, college of animal sciences, Zhejiang University, Hangzhou, China

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Panpan Zhao P Zhao, college of animal sciences, Zhejiang University, Hangzhou, China

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Shuang Li S Li, college of animal sciences, Zhejiang University, Hangzhou, China

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Lieying Xiao L Xiao, college of animal sciences, Zhejiang University, Hangzhou, China

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Shaohua Wang S Wang, college of animal sciences, Zhejiang University, Hangzhou, China

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Kun Zhang K Zhang, college of animal sciences, Zhejiang University, Hangzhou, China

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Tead4, a critical transcription factor expressed during preimplantation development, is essential for the expression of trophectoderm-specific genes in mice. However, the functional mechanism of TEAD4 in mouse preimplantation development and its conservation across mammals remain unclear. Here, we report that Tead4 is a crucial transcription factor necessary for blastocyst formation in mice. Disruption of Tead4 through base editing results in developmental arrest at the morula stage. Additionally, RNA-seq analysis reveals dysregulation of 670 genes in Tead4 knockout embryos. As anticipated, Tead4 knockout led to a decrease in trophectoderm genes Cdx2 and Gata3. Intriguingly, we observed a reduction in Krt8, suggesting that Tead4 influences the integrity of the trophectoderm epithelium in mice. More importantly, we noted a dramatic decrease in nuclear Yap in outside cells for Tead4-deficient morula, indicating that Tead4 directly regulates Hippo signaling. In contrast, bovine embryos with TEAD4 depletion could still develop to blastocysts with normal expression of CDX2, GATA3, and SOX2, albeit with a decrease in total cell number and ICM cell number. In conclusion, we propose that Tead4 regulates mouse blastocyst formation via Krt8 and Yap, both of which are critical regulators of mouse preimplantation development.

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Xiaotong Wu Key Laboratory of Dairy Cow Genetic Improvement and Milk Quality Research of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, China

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Yan Shi Key Laboratory of Dairy Cow Genetic Improvement and Milk Quality Research of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, China

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Bingjie Hu Key Laboratory of Dairy Cow Genetic Improvement and Milk Quality Research of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, China

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Panpan Zhao Key Laboratory of Dairy Cow Genetic Improvement and Milk Quality Research of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, China

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Shuang Li Key Laboratory of Dairy Cow Genetic Improvement and Milk Quality Research of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, China

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Lieying Xiao Key Laboratory of Dairy Cow Genetic Improvement and Milk Quality Research of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, China

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Shaohua Wang Key Laboratory of Dairy Cow Genetic Improvement and Milk Quality Research of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, China

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Kun Zhang Key Laboratory of Dairy Cow Genetic Improvement and Milk Quality Research of Zhejiang Province, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, China

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In brief

Lineage specification plays a vital role in preimplantation development. TEAD4 is an essential transcription factor for trophectoderm lineage specification in mice but not in cattle.

Abstract

Tead4, a critical transcription factor expressed during preimplantation development, is essential for the expression of trophectoderm-specific genes in mice. However, the functional mechanism of TEAD4 in mouse preimplantation development and its conservation across mammals remain unclear. Here, we report that Tead4 is a crucial transcription factor necessary for blastocyst formation in mice. Disruption of Tead4 through base editing results in developmental arrest at the morula stage. Additionally, RNA-seq analysis reveals dysregulation of 670 genes in Tead4 knockout embryos. As anticipated, Tead4 knockout led to a decrease in trophectoderm genes Cdx2 and Gata3. Intriguingly, we observed a reduction in Krt8, suggesting that Tead4 influences the integrity of the trophectoderm epithelium in mice. More importantly, we noted a dramatic decrease in nuclear Yap in outside cells for Tead4-deficient morula, indicating that Tead4 directly regulates Hippo signaling. In contrast, bovine embryos with TEAD4 depletion could still develop to blastocysts with normal expression of CDX2, GATA3, and SOX2, albeit with a decrease in total cell number and ICM cell number. In conclusion, we propose that Tead4 regulates mouse blastocyst formation via Krt8 and Yap, both of which are critical regulators of mouse preimplantation development.

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