Sex Peptide-dependent microcarrier signalling in reproduction

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。用于农业或面临灭绝威胁的动物可以受益于类似的选择性育种方法或增加成功繁殖的机会。越来越多的害虫控制策略是针对生殖，以减少导致疾病或损害作物的昆虫数量。虽然来自雄性的精子对于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，影响雌性生殖器官，如子宫，以提高成功怀孕的机会，在一些动物中，如果蝇，重新编程雌性的大脑，因此，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，这一过程是复杂的，需要对像苍蝇这样简单的动物进行研究才能解开这种复杂性。苍蝇看起来与人类非常不同，但它们拥有我们体内约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的基本机制，如记忆，睡眠和发育，并研究几种主要人类疾病的遗传缺陷，如癌症，糖尿病和阿尔茨海默氏症。开创性的研究表明，精液中一种名为性肽的小苍蝇蛋白质在交配过程中向雌性发送信号方面起着关键作用。它能够大大提高女性的能力，产生后代，使用储存的精子从交配，一个多星期的时间。虽然没有人类的性肽，但控制女性性肽活性的几种分子属于在人类精液中也发现的蛋白质家族。此外，我们最近表明，性肽是储存和交付给女性的专门结构称为微载体。微载体的结构由性肽控制，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作用以提高生育能力，可能会提供有关精液蛋白在其他动物（包括人类）中执行生殖功能的一般机制的线索。我们现在将使用我们在苍蝇中可用的强大技术来研究性肽如何控制微载体结构，将性肽装载在微载体上以在交配期间将其适当地递送给雌性是多么重要，以及哪些其他蛋白质参与微载体依赖性的雄性对雌性的信号传导。我们的实验将确定加载到微载体上的新的精液蛋白质，并揭示它们如何加载以及它们到达雌性时如何分散。他们还将展示这些不同分子和过程的缺陷如何影响女性对精液的不同反应，例如增加产卵，精子储存和拒绝其他男性。我们的研究结果不仅可以让我们建立一个详细的图片解释不同的精液蛋白质如何影响精液的组成和生育力的苍蝇，但他们也将提供重要的线索，类似的分子在其他动物和人类的精液中发挥作用的方式。这可以增强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中的生育能力提出新的方法。这也可能表明在害虫控制技术的设计中阻断昆虫生育力的新方法。

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.