Sex Peptide-dependent microcarrier signalling in reproduction

生殖中性肽依赖性微载体信号传导

• 批准号: BB/W015455/1
• 负责人: Clive Wilson
• 金额: $ 72.91万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW015455%2F1
• 关键词: Sex; Peptide; dependent; microcarrier; signalling

Reproductive biology affects our day-to-day lives in multiple ways. Many patients require assisted reproductive technologies, like in vitro fertilisation, to allow them to have children. Animals used in agriculture or threatened by extinction can benefit from similar approaches for selective breeding or to increase the chances of successful reproduction. Increasingly, pest control strategies are targeting reproduction to reduce numbers of insects that cause disease or damage crops. Although sperm from the male are absolutely essential to fertilise the egg, seminal fluid also has a number of important roles, activating sperm function in females, affecting female reproductive organs, like the uterus, to enhance the chances of a successful pregnancy, and in some animals, like the fruit fly, reprogramming the female's brain, so that she rejects other males who try to mate with her. It is clear that understanding how seminal fluid can produce all these effects is likely to inform development of improved reproductive technologies. However, the processes involved are complex and studies in simple animals like the fly are needed to pick apart this complexity.Flies look very different from humans, but they have equivalents of about 70% of the genes found within us. Perhaps surprisingly, they have frequently been used to unravel the fundamental mechanisms, which control many important biological processes, such as memory, sleep and development, and to study the genetic defects that underlie several major human diseases, such as cancer, diabetes and Alzheimer's. Pioneering studies have shown that a small fly protein in seminal fluid called Sex Peptide plays a pivotal role in sending signals to females during mating. It is able to dramatically increase the female's ability to produce progeny, using stored sperm from the mating, for a period of more than a week. Although there is no human equivalent of Sex Peptide, several molecules that control Sex Peptide's activity in females belong to families of proteins that are also found in human seminal fluid. Furthermore, we have recently shown that Sex Peptide is stored and delivered to females on specialised structures called microcarriers. The structure of microcarriers is controlled by Sex Peptide, but also by a set of enzymes that are very highly evolutionarily conserved in the animal kingdom. Understanding how Sex Peptide and microcarriers co-operate together to enhance fertility is therefore likely to provide clues concerning the general mechanisms by which seminal fluid proteins carry out their reproductive functions in other animals, including humans.We will now use the powerful techniques available to us in flies to work out how Sex Peptide controls microcarrier structure, how critical it is for Sex Peptide to be loaded on microcarriers for it to be properly delivered to females during mating, and what other proteins are involved in microcarrier-dependent, male-to-female signalling. Our experiments will identify new seminal proteins that are loaded on to microcarriers, and reveal how they are loaded and how they are dispersed when they arrive in females. They will also show how defects in these different molecules and processes affect different female responses to seminal fluid, such as increased egg laying, sperm storage and rejection of other males. Our findings will not only allow us to build up a detailed picture explaining how different seminal proteins affect the composition of seminal fluid and fertility in flies, but they will also provide important clues about the ways in which similar molecules perform their roles in seminal fluid of other animals and humans. This could enhance our understanding of male infertility in our own species and in other mammals, and suggest new approaches for optimising fertility in assisted reproductive technologies. It may also indicate new ways of blocking fertility in insects in the design of pest control technologies.

生殖生物学以多种方式影响我们的日常生活。许多患者需要辅助生殖技术，如体外受精，让他们有孩子。用于农业或濒临灭绝的动物可以从类似的选择育种方法或增加成功繁殖的机会中受益。越来越多的害虫控制策略以繁殖为目标，以减少引起疾病或损害作物的昆虫的数量。尽管雄性精子对于使卵子受精是绝对必要的，但精液也有许多重要的作用，激活雌性精子的功能，影响雌性的生殖器官，如子宫，以增加成功怀孕的机会，在一些动物中，如果蝇，重新编程雌性的大脑，使她拒绝其他试图与她交配的雄性。很明显，了解精液如何产生所有这些影响可能会为改进生殖技术的发展提供信息。然而，所涉及的过程是复杂的，需要对像苍蝇这样的简单动物进行研究来分解这种复杂性。苍蝇看起来和人类很不一样，但它们的基因相当于我们体内70%的基因。也许令人惊讶的是，它们经常被用来揭示控制许多重要生物过程（如记忆、睡眠和发育）的基本机制，并用于研究癌症、糖尿病和阿尔茨海默氏症等几种主要人类疾病的遗传缺陷。开创性的研究表明，苍蝇精液中的一种名为“性肽”的小蛋白质在交配时向雌性发送信号方面起着关键作用。它能够极大地提高雌性繁殖后代的能力，利用储存在交配中的精子，持续一个多星期。虽然人类没有与性肽等同的物质，但在女性体内控制性肽活性的几个分子属于在人类精液中也发现的蛋白质家族。此外，我们最近的研究表明，性肽是通过一种叫做微载体的特殊结构储存和传递给雌性的。微载体的结构是由性肽控制的，但也由一组在动物王国中高度进化保守的酶控制。因此，了解性肽和微载体如何共同合作以提高生育能力，可能为精液蛋白在包括人类在内的其他动物中发挥生殖功能的一般机制提供线索。现在，我们将利用现有的强大技术在果蝇中研究出性肽是如何控制微载体结构的，性肽在微载体上的装载对于在交配过程中正确地传递给雌性有多重要，以及其他哪些蛋白质参与了依赖于微载体的雄性对雌性的信号传递。我们的实验将识别装载到微载体上的新精液蛋白，并揭示它们是如何装载的，以及它们到达雌性体内时是如何分散的。他们还将展示这些不同分子和过程中的缺陷如何影响女性对精液的不同反应，如增加产卵、精子储存和排斥其他男性。我们的发现不仅可以让我们建立一个详细的图片来解释不同的精液蛋白是如何影响果蝇精液的组成和生育能力的，而且还将为类似分子在其他动物和人类精液中发挥作用的方式提供重要线索。这将加深我们对人类和其他哺乳动物雄性不育的理解，并为优化辅助生殖技术的生育能力提供新的方法。这也可能在害虫控制技术的设计中指明阻断昆虫繁殖的新方法。

项目成果

A Rab6 to Rab11 transition is required for dense-core granule and exosome biogenesis in Drosophila secondary cells.

• DOI: 10.1371/journal.pgen.1010979
• 发表时间: 2023-10
• 期刊: PLoS genetics
• 影响因子: 4.5