Department of Blood Transfusion, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.
BMC Dev Biol. 2021 Feb 1;21(1):5. doi: 10.1186/s12861-020-00237-x.
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.
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.
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.
脂肪酸氧化在各种发育和成熟的器官系统中起着重要作用。然而，这种代谢途径在睾丸发育的不同阶段的作用尚不清楚。在这里，我们阐明了脂肪酸氧化调节精原细胞和精原干细胞维持和分化的机制。
在 E13.5-E15.5 期间，雄性生殖细胞逐渐进入有丝分裂阻滞阶段，而脂肪酸氧化的限速酶 CPT1A 的表达逐渐增加。因此，我们用 CPT1A 的抑制剂 etomoxir 处理怀孕的老鼠（E13.5 至 E15.5）。用 etomoxir 处理的老鼠在胚胎形态上没有差异；然而，etomoxir 处理的雄性精原细胞退出有丝分裂阻滞，性腺细胞发生凋亡。此外，在 P7 时用 etomoxir 处理的老鼠显示出精原细胞归巢受损和细胞凋亡增加。我们进一步证明，性腺中脂肪酸氧化的抑制与精原细胞分化事件和组蛋白修饰 H3K27ac 有关。
抑制脂肪酸氧化可以特异性降低生殖嵴中 H3K27ac 的水平，这可能是下调雄性分化特异性基因表达的原因，最终导致雄性原始生殖细胞退出有丝分裂阻滞。我们的工作揭示了雄性性腺发育过程中的代谢重编程，表明它在胎儿睾丸发育过程中维持精原细胞处于分化和静止状态中起着重要作用。
