The FecB gene may increase prolificacy by modulating multiple local regulatory pathways

FecB基因可能通过调节多个局部调控途径来提高繁殖力

• 批准号: BB/H014098/1
• 负责人: Bruce Campbell
• 金额: $ 69.25万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH014098%2F1
• 关键词: FecB; gene; may; increase; prolificacy

In certain species (human, sheep, cattle), the number of offspring is tightly regulated to just one or two per pregnancy . The control of offspring number is an extremely important adaption to the physical limits of the mother to bear to term, give birth to and successfully rear young in these species under prevailing environmental conditions. The mechanism whereby offspring number is limited in these so-called monovulatory species involves selection of just one follicle to release an egg (ovulate) per reproductive cycle. The mechanisms controlling follicle development generally, and follicle selection in particular, have been the subject of intensive investigation for many years as they are central to our understanding of the causes and treatment of infertility. A mechanistic model has emerged from these studies that involves the action of local growth factor system (insulin/IGF, inhibin/activin, bone morphogenetic proteins [BMP]) that augment or attenuate the stimulatory role of the pituitary gonadotrophins, LH and FSH, during the terminal gonadotrophin-dependent stages of follicle development (when follicle selection takes place). The sheep has been extensively used as a model species for these studies due to the occurrence of a number of naturally occurring mutations in prolific breeds which lead to varying degrees of disregulation of these selection mechanisms. The Booroola or FecB mutation is one of the most dramatic of these mutations as it results in sheep having up to 6-8 lambs per pregnancy due to complete disregulation of the follicle selection mechanisms. Over recent years, we and others have been able to show that the FecB mutation occurs in the type 1B BMP receptor (BMPR1B). However, the ligands that bind to the BMPR1B and the effect of the FecB mutation on the response of cells within the ovary to stimulation, are not fully understood. On the basis of work we have carried out so it is thought that the BMPR1B interacts with a number of other factors known to be present in the ovary including anti-mullerian hormone (AMH), BMP15 and BMP6. Our mechanistic model of follicle selection therefore predicts that the effect of the Fec B mutation may be due to alteration of the inhibitory or stimulatory effects of one or more of these ligands of the BMPR1B receptor which normally act to augment (BMP-6) and attenuate (BMP-15, AMH) the activity of pituitary gonadotrophins in stimulating the development and selection of ovulatory follicles. This project will utilise a series of highly developed cell culture and whole animal models in combination with advanced molecular techniques to examine this idea by determining: (i) the identity and function of ovarian ligands to the BMPR1B receptor and the effect of the FecB mutation on receptor-ligand interactions and down-stream signalling events in cultured cells; (ii) the effect of increasing or decreasing the activity of ovarian ligands of the BMPR1B receptor on ovarian function in whole animals which do or do not carry the FecB mutation and (iii) if we can replicate the FecB phenotype of multiple small ovulatory follicles in sheep which do not carry the FecB mutation by modulation of the activity of multiple ligands of the BMPR1B. This works brings together the whole animal, cell culture and molecular expertise of experienced investigators in Edinburgh and Nottingham along with the unique availability of the FecB sheep mutant models in order to allow the elucidation of the complex homeostatic interactions between endocrine and local factors that act to regulate this complex and key physiological system. It is expected that this information will add to our fundamental understanding of ovarian function in order to address causes of ovarian disfunction and infertility and to devise innovative means to assess and treat these conditions

在某些物种（人类、绵羊、牛）中，每次怀孕的后代数量被严格控制在一个或两个。在这些物种中，控制后代数量是对母亲的身体限制的一种极其重要的适应，以便在主要的环境条件下生育、生育和成功地养育后代。在这些所谓的单排卵物种中，后代数量有限的机制涉及在每个生殖周期中只选择一个卵泡来释放一个卵子（排卵）。控制卵泡发育的机制，特别是卵泡选择，多年来一直是深入研究的主题，因为它们是我们理解不孕症原因和治疗的核心。从这些研究中出现了一种机制模型，涉及局部生长因子系统（胰岛素/IGF、BMPin/激活素、骨形态发生蛋白[BMP]）的作用，在卵泡发育的终末促性腺激素依赖性阶段（卵泡选择发生时），该系统可增强或减弱垂体促性腺激素、LH和FSH的刺激作用。绵羊已被广泛用作这些研究的模式物种，因为在多产品种中发生了许多自然发生的突变，导致这些选择机制不同程度的失调。Booroola或FecB突变是这些突变中最引人注目的一种，因为它导致绵羊由于卵泡选择机制的完全失调而每次怀孕多达6-8只羔羊。近年来，我们和其他人已经能够证明FecB突变发生在1B型BMP受体（BMPR 1B）中。然而，与BMPR 1B结合的配体以及FecB突变对卵巢内细胞对刺激的反应的影响尚未完全了解。基于我们已经开展的工作，因此认为BMPR 1B与已知存在于卵巢中的许多其他因子相互作用，包括抗苗勒管激素（AMH），BMP 15和BMP 6。因此，我们的卵泡选择机制模型预测Fec B突变的影响可能是由于BMPR 1 B受体的一种或多种配体的抑制或刺激作用的改变，这些配体通常用于增强（BMP-6）和减弱（BMP-15，AMH）垂体促性腺激素刺激排卵卵泡发育和选择的活性。该项目将利用一系列高度发达的细胞培养和整体动物模型，结合先进的分子技术，通过确定以下内容来验证这一想法：（i）BMPR 1B受体的卵巢配体的身份和功能以及FecB突变对培养细胞中受体-配体相互作用和下游信号事件的影响;（ii）增加或降低BMPR 1B受体的卵巢配体的活性对携带或不携带FecB突变的完整动物的卵巢功能的影响，和（iii）如果我们能够通过调节BMPR 1B的多个配体的活性，在不携带FecB突变的绵羊中复制多个小排卵卵泡的FecB表型。这项工作汇集了爱丁堡和诺丁汉经验丰富的研究人员的整个动物，细胞培养和分子专业知识，沿着FecB绵羊突变模型的独特可用性，以便阐明内分泌和局部因素之间的复杂稳态相互作用，这些因素用于调节这种复杂和关键的生理系统。我们期望这些信息将增加我们对卵巢功能的基本了解，以解决卵巢功能障碍和不孕症的原因，并设计创新的方法来评估和治疗这些疾病

项目成果

Reproduction in Domestic Ruminants VIII

家养反刍动物的繁殖 VIII

• 发表时间: 2014
• 作者: Campbell BK, Hernandez-Medrano J, Scaramuzzi RJ, McNeilly AS, Webb R, Picton HM