Embryonic MTHFR contributes to blastocyst development
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EMBRYO BIOLOGY
Embryonic MTHFR contributes to blastocyst development Hiroki Ishitani 1 & Shuntaro Ikeda 2 Naojiro Minami 2 & Takeshi Ohta 1
&
Kai Egashira 1 & Miki Sugimoto 1 & Shinichi Kume 1 &
Received: 1 June 2020 / Accepted: 20 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose Reduction in methylenetetrahydrofolate reductase (MTHFR) activity due to genetic variations in the MTHFR gene has been controversially implicated in subfertility in human in vitro fertilization. However, there is no direct gene-knockdown study of embryonic MTHFR to assess its involvement in mammalian preimplantation development. The purpose of this study is to investigate expression profiles and functional roles of MTHFR in bovine preimplantation development. Methods Reverse transcription-quantitative PCR (RT-qPCR) and analysis of publicly available RNA-seq data were performed to reveal expression levels of MTHFR during bovine preimplantation development. We knocked down MTHFR by siRNAmediated RNA interference from the 8- to 16-cell stage and assessed the effects on preimplantation development. Results The RT-qPCR analysis showed relatively high MTHFR expression at the GV oocyte stage, which was decreased toward the 8- to 16-cell stage and then slightly restored at the blastocyst stage. Public data–based analysis also showed the similar pattern of expression with substantial embryonic expression at the blastocyst stage. MTHFR knockdown reduced the blastocyst rate (P < 0.01) and the numbers of total (P < 0.0001), trophectoderm (P < 0.0001), and inner cell mass (P < 0.001) cells. Conclusion The results indicate that embryonic MTHFR is indispensable for normal blastocyst development. The findings provide insight into the debatable roles of MTHFR in fertility and may be applicable for the improvement of care for early embryos via modulation of surrounding folate-related nutritional conditions in vitro and/or in utero, depending on the parental and embryonic MTHFR genotype. Keywords Folate cycle . MTHFR . Preimplantation . Blastocyst
Introduction Folates are essential nutrients for animals, and folate nutritional status influences various aspects of human reproduction, including ovarian function, preimplantation development, implantation, embryonic and fetal growth and viability, and pregnancy complications [1, 2]. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10815-020-01898-0) contains supplementary material, which is available to authorized users. * Shuntaro Ikeda [email protected] 1
Laboratory of Animal Physiology and Functional Anatomy, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
2
Laboratory of Reproductive Biology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
Cellular folate metabolism consists of an integrated cyclic pathway of enzymatic reactions called the folate cycle which is interlinked to methionine metabolic cycle (Fig. 1) [3]. There are several studies that show
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