Functional dissection of Tmem95: a sperm cell surface protein essential for mammalian fertilization

Tmem95 的功能剖析：哺乳动物受精所必需的精子细胞表面蛋白

• 批准号: BB/T006390/2
• 负责人: Gavin Wright
• 金额: $ 34万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT006390%2F2
• 关键词: Functional; dissection; Tmem95; sperm; cell

In humans, new life starts at fertilization when a sperm and an egg recognise each other and their surrounding membranes fuse to form a new embryo. Sperm and egg interact using cell surface recognition molecules which bind specifically and enable them to fuse together. Although fertilization is a fundamental biological process, our understanding of the molecules involved is remarkably poor, especially in mammals; for example, we do not know the molecule/s that are responsible for fusing the sperm and egg together. These knowledge gaps can be partly explained in humans due to the ethical issues surrounding fertilization, and the difficulties in studying cell surface molecules. For example, eggs are a very rare cell type, with humans usually releasing just a single egg in each fertility cycle limiting the amount of biological material available. In addition, the physical interactions between cell surface molecules are known to be very weak (having half-lives of just seconds), requiring the use of specialised methods to detect them. The Cell Surface Signalling Laboratory at the Sanger Institute specializes in identifying these fleeting interactions and we have developed a set of techniques to circumvent these difficulties. We have previously used these techniques to identify the first essential sperm-egg receptor pair (see Bianchi et al. Nature 2014 v508 p483), which made an important contribution to the molecular understanding of fertilization.We are excited about a new sperm surface protein prosaically named Tmem95 (for TransMEMbrane protein number 95) that is essential for the ability of sperm to fuse with eggs. Tmem95 was identified from research in the cattle industry where a case of idiopathic male infertility (sperm that is infertile despite looking and moving normally) was investigated. Researchers used the results of thousands of artificial inseminations performed in cows, and by careful record-keeping, identified the source to a mutation in the TMEM95 gene. Further research has shown that male mice which have an engineered mutation in their Tmem95 gene are also infertile because normal-looking sperm are unable to fuse with eggs in IVF assays. Humans also have a TMEM95 gene which looks very similar and we believe that it will have an important role in humans too; however, we know very little about this protein. This grant application is aimed at understanding more about the important role TMEM95 has in fertilization. Specifically, we will use our specialized technologies to determine the molecular identity the receptor it interacts with on the egg surface, describe how the protein is redistributed in the sperm during fertilization, establish if Tmem95 has a specific role in fusing membranes together, and investigate how it interacts with another essential sperm cell surface proteins called Izumo1.These studies will both further our molecular understanding of a fundamental biological process, and provide a foundation to develop better contraceptives and fertility treatments both in humans and in the farming industry. The rapidly expanding human population (currently over 7 billion and predicted to reach 10 billion by 2050) has raised concerns that the limited resources on the planet will not sustain a continued expansion. Paradoxically, infertility is a growing problem, particularly in Western countries where the average age of couples having their first child has increased in recent years. By discovering new infertility genes, this research could open up the possibility of offering simple and inexpensive genetic screening tests to infertile couples that may guide their fertility treatment and save the expense and pain of failed rounds of IVF. These studies could also improve reproduction technologies in the livestock industry and also in the development of contraceptive vaccines to control wild animal populations and sterilize companion animals in an ethically more acceptable way other than culling or neutering.

在人类中，新的生命始于施肥，当一个精子和鸡蛋互相识别，其周围的膜融合形成新的胚胎。精子和鸡蛋使用细胞表面识别分子相互作用，这些分子特异性结合并使其融合在一起。尽管受精是一个基本的生物学过程，但我们对所涉及的分子的理解非常差，尤其是在哺乳动物中。例如，我们不知道负责将精子和鸡蛋融合在一起的分子。由于围绕受精的道德问题以及研究细胞表面分子的困难，这些知识差距可以在人类中部分解释。例如，鸡蛋是一种非常罕见的细胞类型，每个生育周期中通常仅释放一个卵，限制了可用的生物材料的量。另外，已知细胞表面分子之间的物理相互作用非常弱（仅半衰期仅几秒钟），需要使用专门的方法来检测它们。 Sanger Institute的细胞表面信号传导实验室专门识别这些短暂的相互作用，我们开发了一套技术来避免这些困难。 We have previously used these techniques to identify the first essential sperm-egg receptor pair (see Bianchi et al. Nature 2014 v508 p483), which made an important contribution to the molecular understanding of fertilization.We are excited about a new sperm surface protein prosaically named Tmem95 (for TransMEMbrane protein number 95) that is essential for the ability of sperm to fuse with eggs.从养牛行业的研究中确定了TMEM95，其中调查了特发性男性不育症的病例（尽管看上去正常和移动）被调查。研究人员使用了在母牛中进行的数千种人工仪的结果，并通过仔细的记录保存确定了TMEM95基因突变的来源。进一步的研究表明，在其TMEM95基因中具有工程突变的雄性小鼠也不育，因为正常的精子无法与IVF分析中的卵融合。人类也有一个TMEM95基因，看起来非常相似，我们认为它在人类中也将发挥重要作用。但是，我们对这种蛋白质一无所知。该赠款的应用旨在更多地了解TMEM95在受精中的重要作用。具体而言，我们将使用我们的专业技术来确定其在卵表面上与其相互作用的受体相互作用的分子身份，描述蛋白质在受精过程中如何重新分布在精子中，确定TMEM95是否在将膜融合在一起中是否具有特定的作用，并与它与另一项必要的精子细胞表面蛋白质相互作用，并将其构成izumoce condure conformention和Thermoc seption and Insultion。在人类和农业行业中开发更好的避孕药具和生育治疗。迅速扩大的人口（目前超过70亿，到2050年预计将达到100亿），这引起了人们的担忧，即地球上有限的资源将无法持续扩张。矛盾的是，不孕症是一个日益严重的问题，尤其是在西方国家，近年来生育孩子的平均年龄有所增加。通过发现新的不孕基因，这项研究可以为可能指导其生育能力的不育夫妇提供简单且廉价的遗传筛查测试的可能性，并节省IVF的失败回合的费用和痛苦。这些研究还可以改善牲畜行业的繁殖技术，以及开发避孕疫苗以控制野生动物种群并以道德上更容易接受的伴侣动物消毒的避孕疫苗，而不是淘汰或绝育。

项目成果

Control of oviductal fluid flow by the G-protein coupled receptor Adgrd1 is essential for murine embryo transit.

• DOI: 10.1038/s41467-021-21512-w
• 发表时间: 2021-02-23
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bianchi E;Sun Y;Almansa-Ordonez A;Woods M;Goulding D;Martinez-Martin N;Wright GJ
• 通讯作者: Wright GJ

Mammalian fertilization: Does sperm IZUMO1 mediate fusion as well as adhesion?

• DOI: 10.1083/jcb.202301035
• 发表时间: 2023-02-06
• 期刊: The Journal of cell biology

Deep learning insights into the architecture of the mammalian egg-sperm fusion synapse

• DOI: 10.1101/2023.07.27.550195
• 发表时间: 2024-02-23
• 期刊: bioRxiv
• 作者: Elofsson，Arne;Han，Ling;Jovine，Luca
• 通讯作者: Jovine，Luca

Editorial: Fertilization in the spotlight: Dynamics and mechanisms of sperm-egg interaction.

• DOI: 10.3389/fcell.2022.993865
• 发表时间: 2022
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5

In silico Docking Analysis for Blocking JUNO-IZUMO1 Interaction Identifies Two Small Molecules that Block in vitro Fertilization.

• DOI: 10.3389/fcell.2022.824629
• 发表时间: 2022
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5