Exosome signalling and cellular reprogramming in the Drosophila reproductive system

在生殖的最初阶段发生的关键事件是一个精子在雌性生殖道内使卵子受精。然而，要实现这一目标，必须克服许多障碍。精子需要在性交后被激活和动员。雌性也会对射精中的外来物质产生免疫反应，精液中的分子必须阻止这种反应。最后，昆虫精液的某些成分会影响雌性的行为，从而增加雄性后代的数量，有证据表明，这也可能发生在哺乳动物身上。在像人类和果蝇这样多种多样的物种中，雄性都有生殖腺，就像男性的前列腺一样，它制造的精液成分参与了这些不同的过程。令人惊讶的是，我们对负责在雄性和雌性交配时传递这些信号的实际分子知之甚少，尽管更好的理解可能会给我们提供与体外受精（IVF）或避孕相关的重要新见解。最近，研究表明，人类前列腺细胞向精液中释放一种叫做外泌体的膜结合结构，至少在培养皿中，这种外泌体可以与精子融合，使精子更具流动性。在一项独立的研究中，我们发现果蝇体内有一个叫做副腺的器官，它分泌果蝇精液中的大部分液体，也会在交配后产生外泌体，在雌性生殖道内与精子融合。这些外泌体在影响雌性的行为方面似乎也很重要，因此雌性对想要与之交配的其他雄性变得不愿接受。幸运的是，过去30年对苍蝇的研究揭示了苍蝇和人类之间惊人的相似之处。在所有已知的与人类疾病有关的基因中，约有70%也在苍蝇身上发现，人类细胞工作的许多基本机制最初是在苍蝇或其他简单生物身上研究的，然后才在人类身上研究。苍蝇和人类之间的相似之处表明，如果我们发现外泌体如何影响苍蝇的繁殖，就可能为我们了解外泌体如何在人类和其他动物中起作用提供重要线索。我们在苍蝇身上的优势在于，我们可以使用一系列显著的实验技巧来标记由活苍蝇的副腺产生的外泌体，选择性地阻断该腺的外泌体分泌，并从外泌体中去除单个成分来测试它们的功能。据我们所知，这是一种全新的方法，目前还没有其他动物可以进行类似的研究。我们将尝试弄清楚是否存在不同类型的外泌体，它们在雌性果蝇中起什么作用，它们是如何针对特定细胞的以及外泌体中的哪些分子会影响目标细胞的行为。我们的发现可能会为人类或动物生殖研究提供重要的新研究角度。例如，如果我们确定了外泌体工作所需的关键分子，就有可能阻断人类体内的等效分子，作为男性避孕策略的一部分，或者在某些男性不育的情况下，如果分子有缺陷，就有可能增强其活性。我们的研究可能还会带来更多的间接好处。例如，外泌体与癌症等疾病有关，它们可能推动肿瘤扩散的一些早期阶段，这是这种疾病最致命的方面。外泌体也被开发为药物的载体，这些药物可以被引入病人体内，并进入像大脑这样难以进入的器官。我们在苍蝇身上的系统确实提供了第一次在活体动物身上解决一些基本问题的机会，这些问题是在所有这些领域工作的科学家们想要回答的，其中一些科学家和我们一起工作，这样他们就可以找到设计实验的最佳方法，并在医学上使用外泌体。

The critical event that takes place in the earliest stages of reproduction is the fertilisation of the egg by a single sperm within the female reproductive tract. However, for this event to happen, a number of hurdles have to be negotiated. Sperm need to be activated and mobilised after intercourse. The female also mounts an immune response to the foreign material in the ejaculate and molecules in the semen must block this. And finally, some components of semen in insects affect female behaviour to increase the number of offspring that a male can produce, and there is some evidence that this could also take place in mammals. In species as diverse as humans and fruit flies, males contain reproductive glands, like the prostate in men, which make the constituents of semen involved in these different processes. Surprisingly, we know little about the actual molecules that are responsible for these signals that pass between males and females when they mate, even though a better understanding might give us important new insights relevant to in vitro fertilisation (IVF) or contraception.Recently, it has been shown that human prostate cells release into semen small membrane-bound structures called exosomes that at least in a petri dish, can fuse to sperm and make them more mobile. In an independent study, we found that an organ in the fruit fly called the accessory gland, which secretes most of the fluid in fly semen, also makes exosomes that fuse with sperm inside the female reproductive tract after mating. These exosomes also seem to be important in affecting the female's behaviour, so that she becomes unreceptive to other males, who want to mate with her. Fortunately studies over the last 30 years in flies have revealed amazing similarities between flies and humans. About 70% of all the genes known to be involved in human disease are also found in flies and lots of the basic mechanisms by which human cells work were originally studied in flies or other simple organisms before being looked at in humans. The parallels between flies and humans suggest that if we find out how exosomes affect reproduction in flies, it is likely to give us important clues about how exosomes work in humans and other animals. The advantage we have in flies is that we can use a remarkable range of experimental tricks to mark the exosomes produced by the accessory gland in living flies, selectively block exosome secretion in this gland and remove individual components from the exosomes to test their function. As far as we are aware, this is a completely new approach and there are no other animals in which similar studies can currently be undertaken. We will try to work out whether there are different types of exosome, what they do in the female fly, how they are targeted to certain cells and which molecules within the exosome affect what the target cell does. Our findings could suggest important new research angles that will then need to be studied in human or animal reproduction. For example, if we identify a key molecule that is needed for exosomes to work, it may be possible to block that equivalent molecule in humans as part of a male contraception strategy or enhance its activity if the molecules is defective in some cases of male infertility. There will probably be additional more indirect benefits from our studies. For example, exosomes have been implicated in diseases, like cancer, where they may drive some of the early stages of tumour spreading, the most lethal aspect of this disease. Exosomes are also being developed as carriers for drugs that could be introduced into patients, and get into inaccessible organs like the brain. Our system in flies really provides the first opportunity in a living animal to address some of the basic questions that scientists working in all these areas, some of whom we work with, wish to answer, so that they can work out the best ways to design their experiments and use exosomes in medicine.