Linking reproductive behaviour and dense core granule biogenesis in secondary cells of the Drosophila male reproductive system

将果蝇雄性生殖系统次生细胞的生殖行为与致密核心颗粒生物发生联系起来

• 批准号: BB/N016300/1
• 负责人: Clive Wilson
• 金额: $ 66.13万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN016300%2F1
• 关键词: Linking; reproductive; behaviour; dense; core

All animals are formed from cells, each with their own functions, which work together to ensure that basic biological processes are kept in balance. To achieve this, neurons and many different cells within glands secrete signals in a controlled way. These signals instruct neighbouring or distant cells to change their behaviour when the normal balance is disturbed or when changes in the environment require the body to adjust accordingly. For example, beta cells in the pancreas secrete more insulin when blood sugar levels are raised, instructing other cells to take up the sugar and restore equilibrium, while nerve-like cells in the adrenal medulla release adrenaline in response to stress to prepare our bodies to fight or run.Cells involved in this regulated form of secretion share common features. They package the hormones or enzymes they release into special compartments, where the molecules are condensed into so-called dense core granules (DCGs) before secretion. Some mechanisms involved have been characterised in detail, but other aspects are poorly understood. For example, how do cells sense that they must rapidly replenish their DCGs after granule release? And how can this be co-ordinated with signals from the environment that alter secretion rates? While answering the first question relies on developing ways of testing how genes control the tiny compartments in which DCGs are formed, these compartments must also be studied in the whole animal to work out how they are affected by the environment. Since DCG control mechanisms go wrong in diseases like diabetes, where insulin secretion is defective, and cancer, where tumour cells signal inappropriately to normal cells around them, understanding how secretion is regulated has the potential to change the way we detect and treat these diseases.We are investigating this problem by studying special prostate-like cells called secondary cells (SCs) in the male reproductive system of the adult fruit fly. It is much easier to study the genetics behind secretion in flies than in animals like mice, and despite the fly's apparent simplicity, it shares remarkable similarities with humans. We have found that SCs have very large DCGs, some of which are released into seminal fluid each time a male fly mates. Mechanisms that control DCG formation in humans seem to be involved in making these compartments in SCs. But we have also found that molecules called BMPs, which are involved in sensing DCG release, instruct SCs to make new compartments, a mechanism that we think is conserved in mammals. In addition, we have been able to use a new type of super-resolution microscopy to watch the giant DCGs form in living glands for the first time, revealing other new features of this process.We now propose to work out the precise way in which BMPs control DCG formation and how brain activity during mating increases the BMP signal so more granules are made. In addition, we will test the importance of some of the new mechanisms for DCG control we have uncovered, such as the delivery of molecules to DCGs on nano-sized vesicles, which are also made by mammalian cells, but have not previously been linked to DCG formation.Overall, our proposed studies will use the unique biology of SCs and our ability to change their secretion using genetics and by mating flies to work out the ways in which different aspects of secretion are controlled in a living animal. Understanding the basic mechanisms involved may also help us to determine how they go wrong in other secreting cells: for example, in diseases like Type 2 diabetes, where faulty secretion leads to imbalance in the body's metabolic control systems, or cancer, where defective secretion can reprogramme normal cells to help tumour cells survive. We have already established collaborative links through our previous studies in flies to take this disease-led work forward as we gain new insights into the ways secretion is controlled from this project.

所有动物都是由细胞组成的，每个细胞都有自己的功能，它们共同努力，以确保基本的生物过程保持平衡。为了实现这一点，神经元和腺体内的许多不同细胞以受控的方式分泌信号。当正常的平衡受到干扰或环境的变化需要身体做出相应的调整时，这些信号会指示邻近或远处的细胞改变它们的行为。例如，当血糖水平升高时，胰腺中的β细胞分泌更多的胰岛素，指示其他细胞摄取糖并恢复平衡，而肾上腺髓质中的神经样细胞则释放肾上腺素以应对压力，使我们的身体做好战斗或逃跑的准备。它们将释放的激素或酶包装到特殊的隔间中，在分泌前，分子被浓缩成所谓的致密核心颗粒（DCG）。其中一些机制已被详细描述，但其他方面知之甚少。例如，细胞如何感觉到它们必须在颗粒释放后迅速补充它们的DCG？这又是如何与来自环境的改变分泌速率的信号相协调的呢？虽然回答第一个问题依赖于开发测试基因如何控制DCG形成的微小隔间的方法，但这些隔间也必须在整个动物中进行研究，以确定它们如何受到环境的影响。由于DCG控制机制在糖尿病（胰岛素分泌缺陷）和癌症（肿瘤细胞向周围正常细胞发出不适当信号）等疾病中出错，了解分泌是如何调节的，有可能改变我们检测和治疗这些疾病的方式。我们正在通过研究称为次级细胞（SC）的特殊前列腺样细胞来研究这个问题。在果蝇的雄性生殖系统中。研究果蝇分泌物背后的遗传学要比研究老鼠等动物容易得多，尽管果蝇表面上很简单，但它与人类有着惊人的相似之处。我们已经发现，SC具有非常大的DCG，其中一些在雄蝇每次交配时释放到精液中。在人类中控制DCG形成的机制似乎参与了在SC中制造这些隔室。但我们也发现，参与感知DCG释放的BMP分子指示SC制造新的隔室，我们认为这是哺乳动物中保守的机制。此外，我们已经能够使用一种新型的超分辨率显微镜来观察巨大的DCG在活体腺体中的形成，这是第一次，揭示了这个过程的其他新特征。我们现在建议找出BMP控制DCG形成的精确方式，以及交配期间的大脑活动如何增加BMP信号，从而产生更多的颗粒。此外，我们将测试我们发现的一些新的DCG控制机制的重要性，例如将分子递送到纳米大小的囊泡上的DCG，这些囊泡也是由哺乳动物细胞制成的，但以前没有与DCG形成联系起来。我们提出的研究将利用SC的独特生物学特性，以及我们利用遗传学和通过交配果蝇来改变其分泌的能力，其中在活体动物中控制分泌的不同方面。了解所涉及的基本机制也可能有助于我们确定它们在其他分泌细胞中是如何出错的：例如，在2型糖尿病等疾病中，分泌缺陷会导致身体代谢控制系统失衡，或者在癌症中，分泌缺陷会导致身体代谢控制系统失衡。重新编程正常细胞以帮助肿瘤细胞生存。我们已经通过我们以前在苍蝇中的研究建立了合作联系，以推进这项疾病主导的工作，因为我们从这个项目中获得了对分泌控制方式的新见解。

项目成果

Accessory ESCRT-III proteins are conserved and selective regulators of Rab11a-exosome formation.

• DOI: 10.1002/jev2.12311
• 发表时间: 2023-03
• 期刊: Journal of extracellular vesicles
• 影响因子: 16

GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain.

• DOI: 10.1038/s41467-021-27056-3
• 发表时间: 2021-11-18
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Dar GH;Mendes CC;Kuan WL;Speciale AA;Conceição M;Görgens A;Uliyakina I;Lobo MJ;Lim WF;El Andaloussi S;Mäger I;Roberts TC;Barker RA;Goberdhan DCI;Wilson C;Wood MJA
• 通讯作者: Wood MJA

Mating Induces Switch From Hormone-Dependent to - Independent Steroid Receptor-Mediated Growth in Drosophila Prostate-Like Cells

交配诱导果蝇前列腺样细胞从激素依赖性生长转变为非类固醇受体介导的生长

• DOI: 10.1101/533976
• 发表时间: 2019
• 作者: Leiblich A

Accessory ESCRT-III proteins selectively regulate Rab11-exosome biogenesis in Drosophila secondary cells

• DOI: 10.1101/2020.06.18.158725
• 发表时间: 2020-06
• 期刊: bioRxiv
• 作者: Pauline P Marie;Shih‐Jung Fan;C. Mendes;M. Wainwright;A. Harris;D. Goberdhan;Clive Wilson

Glutamine Deprivation Regulates the Origin and Function of Cancer Cell Exosomes

• DOI: 10.1101/859447
• 发表时间: 2019-12
• 期刊: bioRxiv
• 作者: Shih‐Jung Fan;Benjamin Kroeger;Pauline P Marie;E. Bridges;John D. Mason;K. McCormick;C. Zois;H. Sheldon;N. K. Alham;Errin Johnson;M. Ellis;M. I. Stefana;C. Mendes;S. Wainwright;C. Cunningham;F. Hamdy;J. Morris;A. Harris;Clive Wilson;D. Goberdhan