Sex Peptide-dependent microcarrier signalling in reproduction

生殖生物学以多种方式影响着我们的日常生活。许多患者需要辅助生殖技术，如体外受精，以允许他们生育。用于农业或面临灭绝威胁的动物可以从类似的选择性繁殖或增加成功繁殖机会的方法中受益。害虫控制策略越来越多地以繁殖为目标，以减少导致疾病或损害作物的昆虫数量。虽然男性的精子对卵子受精是绝对必要的，但精液也有一些重要的作用，激活女性的精子功能，影响女性的生殖器官，如子宫，以增加成功怀孕的机会，在一些动物，如果蝇，重新编程女性的大脑，使她拒绝其他试图与她交配的男性。很明显，了解精液是如何产生所有这些影响的，可能会为改进生殖技术的发展提供信息。然而，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了解这种复杂性。苍蝇看起来与人类非常不同，但它们与我们体内发现的大约70%的基因具有等价性。或许令人惊讶的是，它们经常被用来解开控制记忆、睡眠和发育等许多重要生物过程的基本机制，并研究导致癌症、糖尿病和阿尔茨海默氏症等几种重大人类疾病的基因缺陷。开创性的研究表明，精液中一种名为性肽的小苍蝇蛋白在交配过程中向雌性发送信号方面发挥着关键作用。它能够显著提高雌性交配后代的能力，利用交配后储存的精子，持续一周以上。虽然人类没有性肽的等价物，但有几个控制女性性肽活动的分子属于蛋白质家族，这些蛋白质也存在于人类精液中。此外，我们最近已经证明，性肽是通过称为微载体的特殊结构储存和传递给女性的。微载体的结构由性肽控制，但也受一组在动物界进化上高度保守的酶的控制。了解性肽和微载体如何合作来提高生育力，可能会提供关于精液蛋白在包括人类在内的其他动物身上执行其生殖功能的一般机制的线索。我们现在将利用我们在苍蝇身上可用的强大技术来研究性肽是如何控制微载体结构的，性肽被加载到微载体上对于它在交配过程中正确地传递给雌性有多重要，以及哪些其他蛋白质参与了依赖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的精液蛋白，并揭示它们是如何装载的，以及当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，如产卵增加、精子储存和对其他男性的排斥。我们的发现不仅将使我们能够建立一幅详细的图片，解释不同的精液蛋白如何影响果蝇精液的组成和生育能力，而且它们还将提供关于类似分子如何在其他动物和人类的精液中发挥作用的重要线索。这可能会增强我们对我们自己物种和其他哺乳动物中男性不育症的理解，并为在辅助生殖技术中优化生育能力提供新的方法。这也可能表明在害虫控制技术的设计中阻止昆虫生育的新方法。

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.