Yushan Xu1, Jue Xie2. 1. Department of Blood Transfusion, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China. 2. Department of Blood Transfusion, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China. zyyyxj2011@zju.edu.cn.
Abstract
BACKGROUND: Fatty acid oxidation plays an important role in a variety of developing and mature organ systems. However, the role of this metabolic pathway in different stages of testis development remains unknown. Here, we elucidate the mechanisms by which fatty acid oxidation regulates the maintenance and differentiation of gonocytes and spermatogonial stem cells. RESULTS: During E13.5-E15.5, male germ cells gradually enter the mitotic arrest phase, while the expression of CPT1A, a rate-limiting enzyme for fatty acid oxidation, gradually increases. Therefore, we treated pregnant mice (E13.5 to E15.5) with etomoxir, which is an inhibitor of CPT1A. Etomoxir-treated mice showed no difference in embryonic morphology; however, etomoxir-treated male gonocytes exited mitotic arrest, and cells of the gonad underwent apoptosis. In addition, etomoxir-treated mice at P7 displayed impaired homing of spermatogonia and increased cell apoptosis. We further demonstrated that inhibition of fatty acid oxidation in gonads was associated with gonocyte differentiation events and the histone modification H3K27ac. CONCLUSIONS: Inhibiting fatty acid oxidation can specifically reduce the level of H3K27ac in the reproductive crest, which may be the cause of the down-regulation of male differentiation-specific gene expression, which ultimately leads to the male primordial germ cells exited from mitotic arrest. Our work uncovers metabolic reprogramming during male gonadal development, revealing that it plays an important role in the maintenance of gonocytes in a differentiated and quiescent state during foetal testis development.
BACKGROUND: Fatty acid oxidation plays an important role in a variety of developing and mature organ systems. However, the role of this metabolic pathway in different stages of testis development remains unknown. Here, we elucidate the mechanisms by which fatty acid oxidation regulates the maintenance and differentiation of gonocytes and spermatogonial stem cells. RESULTS: During E13.5-E15.5, male germ cells gradually enter the mitotic arrest phase, while the expression of CPT1A, a rate-limiting enzyme for fatty acid oxidation, gradually increases. Therefore, we treated pregnant mice (E13.5 to E15.5) with etomoxir, which is an inhibitor of CPT1A. Etomoxir-treated mice showed no difference in embryonic morphology; however, etomoxir-treated male gonocytes exited mitotic arrest, and cells of the gonad underwent apoptosis. In addition, etomoxir-treated mice at P7 displayed impaired homing of spermatogonia and increased cell apoptosis. We further demonstrated that inhibition of fatty acid oxidation in gonads was associated with gonocyte differentiation events and the histone modification H3K27ac. CONCLUSIONS: Inhibiting fatty acid oxidation can specifically reduce the level of H3K27ac in the reproductive crest, which may be the cause of the down-regulation of male differentiation-specific gene expression, which ultimately leads to the male primordial germ cells exited from mitotic arrest. Our work uncovers metabolic reprogramming during male gonadal development, revealing that it plays an important role in the maintenance of gonocytes in a differentiated and quiescent state during foetal testis development.
Authors: Jianhua Xiong; Hiroyuki Kawagishi; Ye Yan; Jie Liu; Quinn S Wells; Lia R Edmunds; Maria M Fergusson; Zu-Xi Yu; Ilsa I Rovira; Evan L Brittain; Michael J Wolfgang; Michael J Jurczak; Joshua P Fessel; Toren Finkel Journal: Mol Cell Date: 2018-02-08 Impact factor: 17.970
Authors: Ajit S Divakaruni; Wei Yuan Hsieh; Lucía Minarrieta; Tin N Duong; Kristen K O Kim; Brandon R Desousa; Alexander Y Andreyev; Caitlyn E Bowman; Kacey Caradonna; Brian P Dranka; David A Ferrick; Marc Liesa; Linsey Stiles; George W Rogers; Daniel Braas; Theodore P Ciaraldi; Michael J Wolfgang; Tim Sparwasser; Luciana Berod; Steven J Bensinger; Anne N Murphy Journal: Cell Metab Date: 2018-06-28 Impact factor: 27.287