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/T006390/1
• 负责人: Gavin Wright
• 金额: $ 45.37万
• 依托单位: Wellcome Sanger Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT006390%2F1
• 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，当精子和卵子相互识别，它们周围的膜融合形成新的胚胎时，新的生命开始于受精。精子和卵子通过细胞表面识别分子相互作用，这种分子特定地结合在一起，使它们能够融合在一起。虽然受精是一个基本的生物过程，但我们对其中涉及的分子的了解非常糟糕，特别是在哺乳动物中；例如，我们不知道负责将精子和卵子融合在一起的分子/S。这些知识差距可以在一定程度上解释人类，因为围绕受精的伦理问题，以及研究细胞表面分子的困难。例如，卵子是一种非常罕见的细胞类型，人类通常在每个生育周期只释放一个卵子，限制了可用的生物材料的数量。此外，众所周知，细胞表面分子之间的物理相互作用非常弱(半衰期只有几秒钟)，需要使用专门的方法来检测它们。桑格研究所的细胞表面信号实验室专门识别这些短暂的相互作用，我们已经开发了一套技术来绕过这些困难。我们以前曾使用这些技术来识别第一个基本的精子-卵子受体对(见Bianci等人。我们对一种新的精子表面蛋白TMEM95(跨膜蛋白编号95)感到兴奋，它对精子与卵子融合的能力至关重要。TMEM95是从养牛行业的研究中确定的，该行业调查了一例特发性男性不育(尽管看起来和运动正常，但精子仍然不育)。研究人员使用了数千头在奶牛身上进行的人工授精的结果，并通过仔细保存记录，确定了TMEM95基因突变的来源。进一步的研究表明，具有TMEM95基因工程突变的雄性小鼠也是不育的，因为在试管受精测试中，看起来正常的精子无法与卵子融合。人类也有一个看起来非常相似的TMEM95基因，我们相信它将在人类中发挥重要作用；然而，我们对这种蛋白质知之甚少。这项资助申请旨在更多地了解TMEM95在受精中的重要作用。具体地说，我们将使用我们的专门技术来确定它与鸡蛋表面受体相互作用的分子身份，描述这种蛋白质在受精过程中如何在精子中重新分布，确定TMEM95是否在融合膜方面具有特定的作用，并研究它如何与另一种名为Izumo1的基本精子细胞表面蛋白相互作用。这些研究将加深我们对基本生物学过程的分子理解，并为在人类和农业中开发更好的避孕和生育治疗方法提供基础。快速增长的人口(目前超过70亿，预计到2050年将达到100亿)引发了人们的担忧，即地球上有限的资源将无法持续增长。矛盾的是，不孕不育是一个日益严重的问题，特别是在西方国家，近年来夫妇生育第一个孩子的平均年龄有所增加。通过发现新的不孕基因，这项研究可能会为不育夫妇提供简单而廉价的基因筛查测试，从而指导他们的生育治疗，并省去失败的几轮试管受精的费用和痛苦。这些研究还可以改进畜牧业的繁殖技术，也可以改进避孕疫苗的开发，以控制野生动物种群，并以伦理上更容易接受的方式为同伴动物绝育，而不是扑杀或绝育。

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

Same gene, opposite sexes: Sex-specific divergent expression of a gene required for vertebrate fertilization.

• DOI: 10.1073/pnas.2116001118
• 发表时间: 2021-10-19
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Bianchi E

Find and fuse: Unsolved mysteries in sperm-egg recognition.

• DOI: 10.1371/journal.pbio.3000953
• 发表时间: 2020-11
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Bianchi E;Wright GJ
• 通讯作者: Wright GJ

Control of fluid flow by Adgrd1 is essential for mammalian oviductal embryo transport

Adgrd1 对流体流动的控制对于哺乳动物输卵管胚胎运输至关重要

• 发表时间: 2020
• 期刊: BioRxiv
• 作者: Bianchi, E

No evidence for a direct extracellular interaction between human Fc receptor-like 3 (MAIA) and the sperm ligand IZUMO1

• DOI: 10.1126/sciadv.adk6352
• 发表时间: 2024-02-21
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Bianchi，Enrica;Jimenez-Movilla，Maria;Wright，Gavin J.
• 通讯作者: Wright，Gavin J.