Effects of maternal-gene mutations on phenotypes of wild-type progeny

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07144
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Furuse Tamio 国立研究開発法人理化学研究所, バイオリソース研究センター, 開発研究員 (60392106)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: DOHaD / マウス行動解析 / 実験動物 / Mat2a / One carbon metabolism

Outline of Final Research Achievements

The OCM is consisted of methionine cycle and folate cycle. The folate cycle is involved in DNA synthesis and the methionine cycle is involved in DNA methylation by donating methyl group. In the present study, we aimed to evaluate effects of maternal OCM deficit on neurobehavioral phenotypes of progeny. In order to evaluate the effects of Mat2a mutation on nutritional environment of the fetuses, we performed LC-MS measurements of OCM metabolites in plasma of heterozygote of the Mat2a mutants and wild type mice. The pre-pregnancy females of the Mat2a mutants exhibited decreased concentration of S-adenosyl methionine (SAM). We transferred C57BL/6N embryo to uteruses of wild type and heterozygous Mat2a knockout (Mat2a mutant) females. The offspring from the Mat2a mutants exhibited increased locomotor activity and deficits of fear conditioned learning. These results suggest that the exposure to decreased SAM level during early to middle pregnancy affects brain function of progenies.

Free Research Field

実験動物学

Academic Significance and Societal Importance of the Research Achievements

生育環境が成人した後の疾患感受性に影響を与えるという概念はDevelopmental Origins of Health and Disease (DOHaD)と呼ばれ、精神疾患分野においても生物学的メカニズムの解明が求められている。
本研究により、マウスにおいては、母体のOCM 関連遺伝子Mat2aの変異が次世代の遺伝子変異を持たないマウスの行動表現型や遺伝子発現に影響を与えることが明らかになった。このことから、ヒトにおいて母体のOCM関連遺伝子の変異が次世代に伝達しない場合においても、次世代の疾患感受性に影響する可能性が示唆され、上記のDOHaD研究の進展に寄与することが期待される。