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.

通过在发育中的卵巢中形成一系列原始卵泡，在胎儿生活中建立了女性生殖寿命。原始卵泡由卵（卵母细胞）组成，这些卵（卵母细胞）被一层颗粒前细胞包围，这些卵母细胞支持，维持和控制卵母细胞的生长。妇女天生有有限数量的卵泡，这些卵泡在一生中的数量下降，并且出生后没有形成新的卵泡。更年期发生在卵泡储备耗尽时，通常发生在50岁左右。但是，在1％的女性中，更年期发生在40岁之前，这种情况称为早产卵巢不足（POI）。除了对尚未完成家人的妇女诊断外，POI还与重大的绝经后健康风险有关，例如骨质疏松症和心血管疾病。此外，随着社会趋势越来越多地朝着以后的生活家庭发展，并且随着年龄的增长，卵巢中的卵母细胞的供应和质量下降，经历超级生育的妇女数量可能会增加。尽管卵泡形成过程至关重要，在建立人类和其他哺乳动物（例如牲畜物种）中建立生殖寿命，但我们对胎儿卵巢中卵泡的库存是如何形成的。如果我们要调查遗传，环境或生活方式因素如何破坏卵泡形成并减少生殖寿命，那么提高我们对这个基本过程的了解至关重要。细胞到细胞信号分子激活素A（ACTA）是卵泡形成的可能的关键调节剂。胎儿/新生小鼠卵巢中的ACTA信号升高导致形成更多原始卵泡。发生这种情况的机制尚不清楚，但很可能涉及颗粒前细胞数或行为的变化，因为ACTA仅信号在发育中的卵巢中对此细胞类型的信号。颗粒前细胞还表达了一种称为FOXL2的蛋白质，该蛋白质激活对卵巢发育很重要的基因。在人类中，FOXL2基因的突变会导致POI，不育症和颗粒细胞肿瘤（一种罕见的卵巢癌）。在小鼠中，缺乏FOXL2的颗粒前细胞无法正常工作，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共同起作用，以激活细胞需要反应和产生生殖激素所需的基因，而相似的FOXL2/ACTA相互作用会激活成人卵巢的颗粒细胞中的基因。然而，尚不清楚ACTA和FOXL2是否共同调节胎儿卵巢中的颗粒前细胞功能和卵泡形成。该项目的目的是使用新生小鼠卵巢和人类颗粒前细胞作为模型来解决这个问题。我们将确定在卵巢中形成的表达FOXL2的前颗粒细胞的数量是否会限制可以形成的卵泡数，并确定激活素是否通过改变颗粒前细胞池的大小来增加卵泡数量。为了深入了解它们在颗粒前细胞中调节的生化过程，我们将确定ACTA和FOXL2联合控制的基因，并研究任何因素的丢失是否会阻止这些基因正确打开或关闭。最后，我们将调查为什么原始卵泡在FOXL2缺陷型小鼠卵巢中未正确形成，确定激活素（或其他信号）的异常信号是该缺陷的原因，并确定是否可以通过恢复细胞之间的正常信号来纠正这种缺陷。这些研究将为建立卵泡数量（以及女性生殖寿命）的数量提供新的启示，提供有关人类FOXL2突变如何导致不育的洞察力，并告知未来的研究以发展新的生育策略。