SHMT2 is essential for mammalian preimplantation embryonic development through de novo biosynthesis of nucleotide metabolites

Mingze Shi; Yingxue Huai; Tiantian Deng; Chuanxin Zhang; Jinzhu Song; Jiawei Wang; Yiwen Zhang; Zi-Jiang Chen; Han Zhao; Keliang Wu; Boyang Liu

Molecular Therapy: Nucleic Acids (Jun 2025)

SHMT2 is essential for mammalian preimplantation embryonic development through de novo biosynthesis of nucleotide metabolites

Mingze Shi,
Yingxue Huai,
Tiantian Deng,
Chuanxin Zhang,
Jinzhu Song,
Jiawei Wang,
Yiwen Zhang,
Zi-Jiang Chen,
Han Zhao,
Keliang Wu,
Boyang Liu

Affiliations

Mingze Shi: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China
Yingxue Huai: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China
Tiantian Deng: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China
Chuanxin Zhang: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China
Jinzhu Song: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China
Jiawei Wang: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China
Yiwen Zhang: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China
Zi-Jiang Chen: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China
Han Zhao: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China
Keliang Wu: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China; Corresponding author: Keliang Wu, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China.
Boyang Liu: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong 250012, China; Corresponding author: Boyang Liu, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong 250012, China.

Journal volume & issue: Vol. 36, no. 2
p. 102499

Abstract

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Assisted reproductive technology (ART) is used widely and efficiently to treat infertility. During the ART procedure, one of the main factors affecting the success rate is abnormal development of preimplantation embryos. The establishment and maintenance of developmental competence are precisely regulated at different levels, while minor errors at early stages may result in adverse outcomes, including developmental arrest and implantation failure. As one of the major inputs, the regulatory mechanisms of metabolites in embryonic development are less known. In this study, we investigated the functional relevance of the metabolic enzyme serine hydroxymethyltransferase 2 (SHMT2) and deoxyribonucleotide (dNTP) metabolites in mouse preimplantation embryonic development. By using a well-characterized SHMT2 inhibitor, SHMT-IN-2, we effectively inhibited the catalytic activity of the SHMT2 enzyme, which led to developmental arrest at the pronuclear stage of the embryo. A low-input liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and applied for detecting dNTP content in embryos. We found that SHMT2 inhibition led to an insufficient dTTP supply and replication stress during the first mitotic cleavage, thereby causing failure of pronuclear fusion and developmental arrest. Our findings demonstrate a specific mechanism where, apart from building blocks of DNA, the availability of dNTPs contributes to the control of mouse preimplantation embryonic development.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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