Co-ordinated regulation of ovarian follicle assembly by Activin A and FoxL2

激活素 A 和 FoxL2 对卵泡组装的协调调节

• 批准号: BB/P003435/1
• 负责人: Andrew Childs
• 金额: $ 45.84万
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP003435%2F1
• 关键词: Co; ordinated; regulation; ovarian; follicle

Female reproductive lifespan is established during fetal life through the formation of a cohort of primordial follicles in the developing ovary. Primordial follicles consist of an egg (oocyte) surrounded by a layer of pre-granulosa cells, which support, maintain and control the growth of the oocyte. Women are born with a finite number of follicles which decline in number throughout life, and no new follicles are formed after birth. The menopause occurs when the follicular reserve is exhausted, which normally happens around the age of 50. However, in 1% of women the menopause occurs before the age of 40, a condition known as premature ovarian insufficiency (POI). In addition to being a devastating diagnosis for women yet to complete their families, POI is associated with significant post-menopausal health risks, such as osteoporosis and cardiovascular disease. Furthermore, as societal trends move increasingly towards starting families later in life, and the supply and quality of oocytes in the ovary declines with age, the number of women experiencing sub-fertility is likely to rise. Despite the critical importance of the follicle formation process in establishing reproductive lifespan in humans, and other mammals (such as livestock species), we know very little about how the stock of follicles is formed in the fetal ovary. Improving our knowledge of this fundamental process is essential if we are to investigate how genetic, environmental or lifestyle factors can disrupt follicle formation and curtail reproductive lifespan. The cell to cell signalling molecule Activin A (ActA) is a possible key regulator of follicle formation. Elevated ActA signalling in fetal/neonatal mouse ovaries results in the formation of greater numbers of primordial follicles. The mechanism by which this occurs is unclear, but is likely to involve changes to pre-granulosa cell number or behavior, as ActA only signals to this cell type in the developing ovary. Pre-granulosa cells also express a protein called FoxL2, which activates genes important for ovarian development. In humans, mutations in the FOXL2 gene cause POI, infertility and granulosa cell tumours (a rare type of ovarian cancer). In mice, pre-granulosa cells that lack FoxL2 cannot function correctly, and so fail to form follicles (or form follicles that cannot mature). In the pituitary gland, ActA and FoxL2 work together to activate genes that are required for cells to respond to, and produce, reproductive hormones, and a similar FoxL2/ActA interaction activates genes in the granulosa cells of the adult ovary. Whether ActA and FoxL2 work together to regulate pre-granulosa cell function and follicle formation in the fetal ovary is not known, however. The aim of this project is to address this question, using the neonatal mouse ovary and human pre-granulosa cells as models. We will establish whether the number of FoxL2-expressing pre-granulosa cells formed in the ovary limits the number of follicles that can be formed, and determine whether activin increases follicle number by altering the size of the pre-granulosa cell pool. To gain insight into the biochemical processes they regulate in pre-granulosa cells, we will identify the genes that ActA and FoxL2 jointly-control, and investigate whether loss of either factor prevents these genes from being switched on or off correctly. Finally, we will investigate why primordial follicles fail to form correctly in FoxL2-deficient mouse ovaries, determine whether aberrant signalling by activin (or other signals) is the cause of this defect, and establish whether this can be corrected by restoring normal levels of signalling between cells. These studies will shed new light on how the number of follicles (and thus female reproductive lifespan) is established, provide insight into how mutations in FOXL2 in humans lead to infertility, and inform future studies to develop of new strategies to manage fertility.

女性的生殖寿命是在胎儿时期通过发育中的卵巢中一群原始卵泡的形成而确定的。原始卵泡由卵子（卵母细胞）组成，周围有一层前颗粒细胞，支持、维持和控制卵母细胞的生长。女性生来就有有限数量的卵泡，并且在一生中数量会不断减少，并且出生后不会形成新的卵泡。当卵泡储备耗尽时，就会进入更年期，通常发生在 50 岁左右。然而，有 1% 的女性在 40 岁之前就进入更年期，这种情况称为卵巢早衰 (POI)。除了对尚未组建家庭的女性来说，POI 是一种毁灭性的诊断之外，POI 还与重大的绝经后健康风险相关，例如骨质疏松症和心血管疾病。此外，随着社会趋势越来越倾向于晚育，卵巢中卵母细胞的供应和质量随着年龄的增长而下降，生育力低下的女性人数可能会增加。尽管卵泡形成过程对于人类和其他哺乳动物（例如牲畜物种）的生殖寿命至关重要，但我们对胎儿卵巢中卵泡的形成方式知之甚少。如果我们要研究遗传、环境或生活方式因素如何破坏卵泡形成并缩短生殖寿命，那么提高我们对这一基本过程的了解至关重要。细胞间信号分子激活素 A (ActA) 可能是卵泡形成的关键调节因子。胎儿/新生小鼠卵巢中 ActA 信号传导升高导致形成更多数量的原始卵泡。发生这种情况的机制尚不清楚，但可能涉及前颗粒细胞数量或行为的变化，因为 ActA 仅向发育中的卵巢中的这种细胞类型发出信号。前颗粒细胞还表达一种名为 FoxL2 的蛋白质，该蛋白质可激活对卵巢发育重要的基因。在人类中，FOXL2 基因突变会导致 POI、不孕症和颗粒细胞瘤（一种罕见的卵巢癌）。在小鼠中，缺乏 FoxL2 的前颗粒细胞无法正常发挥作用，因此无法形成卵泡（或形成无法成熟的卵泡）。在垂体中，ActA 和 FoxL2 共同激活细胞响应和产生生殖激素所需的基因，并且类似的 FoxL2/ActA 相互作用激活成体卵巢颗粒细胞中的基因。然而，ActA 和 FoxL2 是否共同作用来调节胎儿卵巢中的前颗粒细胞功能和卵泡形成尚不清楚。该项目的目的是使用新生小鼠卵巢和人类前颗粒细胞作为模型来解决这个问题。我们将确定卵巢中形成的表达 FoxL2 的前颗粒细胞数量是否限制了可形成的卵泡数量，并确定激活素是否通过改变前颗粒细胞池的大小来增加卵泡数量。为了深入了解它们在前颗粒细胞中调节的生化过程，我们将鉴定 ActA 和 FoxL2 共同控制的基因，并研究任一因子的丢失是否会阻止这些基因正确打开或关闭。最后，我们将研究为什么 FoxL2 缺陷的小鼠卵巢中原始卵泡无法正确形成，确定激活素（或其他信号）的异常信号传导是否是这种缺陷的原因，并确定是否可以通过恢复正常的信号水平来纠正这种缺陷细胞之间。这些研究将为卵泡数量（以及女性生殖寿命）的确定提供新的线索，深入了解人类 FOXL2 突变如何导致不孕，并为未来研究制定管理生育的新策略提供信息。