How do Fbxo7 and PI31 control sperm morphogenesis and male fertility?

Fbxo7 和 PI31 如何控制精子形态发生和男性生育能力？

• 批准号: BB/X014177/1
• 负责人: Heike Laman
• 金额: $ 69.68万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX014177%2F1
• 关键词: How; do; Fbxo7; PI31; control; How; do; Fbxo7; PI31; control

Sperm cells are the smallest cells in the body, having shed virtually all of their cellular contents in order to swim faster. The production of mature sperm thus involves perhaps the most radical changes in cellular shape in all of mammalian biology. As sperm cells develop, they are dragged into deep indentations ("crypts") within nurse cells (Sertoli cells) that support and sculpt them. Therein, developing sperm cells make ready their cytoplasm for elimination, and package it up for disposal by the Sertoli cells. As the sperm realise their final shape, they are pushed back out of the crypts, and finally released as free-living, mature sperm cells. As yet, little is understood about the processes that coordinate this transformation and control how each cell is moulded into its final shape. We recently discovered that a protein called Fbxo7 is critical for sperm remodelling at a precise time in the process of assuming this streamlined shape. In male mice that lack Fbxo7, sperm cells develop normally up to the point where they enter the crypts - however the cells never leave the crypts and instead all die at once. This shows that Fbxo7 is necessary for the cellular remodelling steps to make a sperm. We know that Fbxo7 plays a role in maintaining the function of mitochondria - which supply cells with energy - and in disposing of defective mitochondria. Fbxo7 performs many of its functions by adding a small tag, called ubiquitin, onto other "target" proteins. This ubiquitin tag usually causes the target proteins to be disposed of by a large degrading enzyme called the proteasome, but in some cases, it can alter the target protein's function or move it around the cell. Fbxo7 also interacts with a partner protein called PI31 that attaches proteasomes to motor proteins to move them around within a cell. Our findings suggest that the addition of ubiquitin to target proteins by Fbxo7, with or without the help of its partner PI31, is likely to be akey factor in regulating mitochondria and/or proteasome trafficking inside the cell during the final phase of sperm remodelling.Our key goals are:1. To find out what is going wrong in the testes of males lacking Fbxo7 and PI31 - are the mitochondria fragmented or deformed, are they being carried to the right location within the cell, and are they working normally? Alternatively, is there a problem with proteasome localisation? We will investigate this using fluorescence microscopy and electron microscopy in conjunction with staining for markers of each of these processes.2. To identify what Fbxo7 is doing biochemically in normal testes - what is it attaching ubiquitin to, and what effect does this have? Does it require help from PI31? What proteins associate with proteasomes when sperms are being sculpted and how is this controlled by Fbxo7 and PI31. We will investigate this by comparing the ubiquitin-tagged proteins and the proteasome-associated proteins in cells from mice lacking Fbxo7 and PI31.Understanding how these events take place is important from both a pure science and a medical perspective - for example, understanding Fbxo7 function may help us understand and eventually treat sterility in some infertile patients who make no sperm. Conversely, selectively interfering with Fbxo7 function in the testes could become the basis for novel methods of male contraception. Fbxo7 is also important in other tissues: many different cell types such as red blood cells and nerve cells also undergo remodelling to transform their shapes, and Fbxo7 deficiency is also associated with anaemia and neurological conditions such as Parkinson's disease. Understanding how Fbxo7 and PI31 control cell shape in the testis may shed light on their role(s) in these other diseases as well.

精子细胞是体内最小的细胞，几乎将其所有细胞含量脱落，以便更快地游泳。因此，成熟精子的产生涉及所有哺乳动物生物学中细胞形状的最根本变化。随着精子细胞的发展，它们被拖入支持和雕刻它们的护士细胞（Sertoli细胞）内的深凹痕（“隐窝”）。在其中，发育的精子细胞使他们的细胞质做好了消除，并将其包装为Sertoli细胞处置。当精子意识到其最终形状时，它们被推回了隐窝，最后将其释放为自由生活的成熟精子细胞。到目前为止，关于协调这种转换的过程并控制每个细胞如何模制成最终形状的过程，几乎没有理解。我们最近发现，一种称为FBXO7的蛋白质对于在假定这种简化形状的过程中精确的时间进行精子重塑至关重要。在缺乏FBXO7的雄性小鼠中，精子细胞正常发育直到进入隐窝性 - 但是细胞永远不会离开隐窝，而是一次死亡。这表明FBXO7对于蜂窝重塑步骤以制造精子是必需的。我们知道，FBXO7在维持线粒体的功能中起作用 - 供应细胞为能量提供能量 - 以及处置有缺陷的线粒体。 FBXO7通过在其他“靶”蛋白上添加一个称为泛素的小标签（称为泛素）来执行许多功能。这种泛素标签通常会导致靶蛋白被称为蛋白酶体的大降解酶处理，但在某些情况下，它可以改变靶蛋白的功能或将其移动在细胞周围。 FBXO7还与称为PI31的伴侣蛋白相互作用，该蛋白将蛋白酶体连接到运动蛋白上，以将其移动到细胞中。我们的发现表明，在有或没有其伴侣pi31的帮助下，通过FBXO7将泛素添加到靶蛋白中，可能是调节线粒体和/或蛋白酶体在精子重塑的最后阶段内部进行线粒体和/或蛋白酶体运输的因素。我们的主要目标是：1：1。要找出缺乏FBXO7和PI31的雄性睾丸的问题 - 线粒体是否碎片或变形，它们是否被携带到细胞内正确的位置，并且它们是否正常工作？另外，蛋白酶体定位是否存在问题？我们将使用荧光显微镜和电子显微镜与每个过程的标记染色结合进行研究。2。要识别正常睾丸中FBXO7在生物化学上做什么 - 它将泛素连接到什么，这有什么影响？它需要PI31的帮助吗？当精子被雕刻时，哪种蛋白与蛋白酶体相关，以及如何由FBXO7和PI31控制。我们将通过比较缺乏FBXO7和PI31的小鼠中细胞中的泛素标记的蛋白质以及与蛋白酶体相关的蛋白质进行调查。理解这些事件的发生是从纯科学和医学角度重要的重要性 - 例如，理解FBXO7的功能可能会帮助您理解并最终使无症患者理解并最终对某些spttile ssptipile进行治疗。相反，在睾丸中有选择地干扰FBXO7功能可能成为新型男性避孕方法的基础。 FBXO7在其他组织中也很重要：许多不同的细胞类型（例如红细胞和神经细胞）也经历重塑以改变其形状，而FBXO7缺乏症也与贫血和神经系统疾病（如帕金森氏病）有关。了解睾丸中的FBXO7和PI31控制细胞形状如何揭示其在这些其他疾病中的作用。