John George B, Shidler Meredith J, Besmer Peter, Castrillon Diego H
Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, 75390-9072, USA.
Dev Biol. 2009 Jul 15;331(2):292-9. doi: 10.1016/j.ydbio.2009.05.546. Epub 2009 May 15.
In mammals, primordial follicles are generated early in life and remain dormant for prolonged intervals. Their growth resumes via a process known as primordial follicle activation. Recent genetic studies have demonstrated that phosphoinositide 3-kinase (PI3K) is the essential signaling pathway controlling this process throughout life, acting via Akt to regulate nucleocytoplasmic shuttling of Foxo3, which functions as a downstream molecular switch. The receptor tyrosine kinase Kit has been implicated by numerous studies as the critical upstream regulator of primordial follicle activation via PI3K/Akt. Here we present a genetic analysis of the contribution of Kit in regulating primordial follicle activation and early follicle growth, employing a knock-in mutation (Kit(Y719F)) that completely abrogates signaling via PI3K. Surprisingly, homozygous Kit(Y719F) female mice undergo primordial follicle activation and are fertile, demonstrating that Kit signaling via PI3K is dispensable for this process. However, other abnormalities were identified in Kit(Y719F) ovaries, including accelerated primordial follicle depletion and accumulation of morphologically abnormal primary/secondary follicles with persistent nuclear Foxo3 localization. These findings reveal specific roles of Kit in the maintenance of the primordial follicle reserve and in the primary to secondary follicle transition, but argue that Kit is dispensable in primordial follicle activation.
在哺乳动物中，原始卵泡在生命早期形成，并长时间处于休眠状态。它们通过一个称为原始卵泡激活的过程恢复生长。最近的遗传学研究表明，磷酸肌醇3-激酶（PI3K）是终生控制这一过程的关键信号通路，通过Akt调节Foxo3的核质穿梭，Foxo3作为下游分子开关发挥作用。众多研究表明，受体酪氨酸激酶Kit是通过PI3K/Akt途径激活原始卵泡的关键上游调节因子。在此，我们利用完全消除PI3K信号传导的敲入突变（Kit(Y719F)），对Kit在调节原始卵泡激活和早期卵泡生长中的作用进行了遗传学分析。令人惊讶的是，纯合Kit(Y719F)雌性小鼠经历了原始卵泡激活且具有生育能力，这表明通过PI3K的Kit信号传导在这一过程中是可有可无的。然而，在Kit(Y719F)卵巢中发现了其他异常情况，包括原始卵泡加速耗竭以及形态异常的初级/次级卵泡积累，且核内Foxo3持续定位。这些发现揭示了Kit在维持原始卵泡储备以及初级卵泡向次级卵泡转变中的特定作用，但表明Kit在原始卵泡激活中是不必要的。
