Functional significance and remodeling challenges of polyploidy across the lifetime of epithelial tissues

动物细胞具有支持其生物学作用的特征结构。例如，上皮细胞紧密粘附到它们的邻居以形成组织片，这是一种支持屏障功能的结构，例如皮肤作为外部保护层或肠道衬里。细胞结构的一个方面是细胞核及其大小。虽然大多数细胞是二倍体，每个亲本都有一个基因组拷贝，但某些细胞会变成多倍体，在单个细胞核内有许多基因组拷贝。这导致大的细胞核和成比例的大细胞。多倍体的好处和代价是什么？多倍体细胞存在于肝脏、肌肉、母体和胚胎外组织中，例如在母体-胎儿界面支持胎盘发育的组织。益处包括创伤后的屏障组织维护和修复。伤口修复涉及多倍体细胞变得更大，以帮助覆盖伤口部位。此外，拥有多个基因组拷贝有助于快速、有效地生产所需的蛋白质，例如从促进母乳生产的胎盘基因中生产。然而，DNA拷贝数和实际蛋白质输出之间并不总是存在明确的相关性，并且在实验条件下，一些组织似乎也可以在不是多倍体的情况下发挥功能。因此，需要对其他组织类型进行研究，以更好地理解多倍性的假设益处。另一方面，多倍性也对细胞提出了挑战。在某些情况下，整个细胞的基因组不会被复制，而只是包含某些基因的DNA区域。当只需要来自这些基因的特定蛋白质时，这是支持快速生产的有效方法。然而，DNA拷贝的这种部分增加是一种不稳定的排列，通常会触发程序性细胞死亡，称为细胞凋亡，作为生物质量控制的一种形式。因此，多倍体细胞需要特殊的遗传特性来抑制这一点。一个关键的研究系统，这已经探索是果蝇黑腹果蝇，一个强大的遗传学模型物种。然而，我们发现控制程序性细胞死亡的关键基因，即所谓的死神基因，是苍蝇的一个独特特征。目前尚不清楚哪些基因在其他动物中发挥这种功能。此外，癌细胞的一个标志是它们具有不稳定的DNA排列，但以某种方式逃避程序性细胞死亡。在新物种中对多倍体细胞如何处理程序性细胞死亡问题的研究将确定关键基因，并有助于提高我们对癌症治疗相关遗传学的理解。（屏障组织结构，快速蛋白质生产）并检查潜在风险（不稳定的DNA排列，需要阻止细胞死亡）的多倍体在一个新的生物系统：两个胚外组织的面粉甲虫赤拟谷盗。这些组织通过包围和保护胚胎来发挥上皮屏障功能。浆膜包围着胚胎和蛋黄，而羊膜，就像哺乳动物中的羊膜一样，形成了一个充满液体的内腔。浆膜也有一个快速生产的作用，使角质层，加强蛋壳。值得注意的是，这些组织在其一生的大部分时间内都是稳定的和多倍体的，然后它们主动暴露胚胎并精确地经历细胞死亡。我们已经开发了研究甲虫多倍体的方法，包括基因组测序和实时成像显微镜，揭示了健康和实验扰动的屏障组织结构。浆膜和羊膜提供了一个很好的比较系统。我们的初步工作表明，浆膜是能够增加多倍性，以弥补在遗传模型的伤口样组织损伤，而羊膜不是。这为更好地理解多倍体的组织特异性特征和发现参与多倍体控制的新的关键基因铺平了道路。

Animal cells have characteristic structures that support their biological roles. For example, epithelial cells adhere tightly to their neighbors to form sheets of tissue, a structure that supports barrier functions such as with the skin as an outer protective layer, or the lining of the gut. One aspect of cell structure is the nucleus and its size. While most cells are diploid, with a copy of the genome from each parent, certain cells become polyploid, with many copies of the genome within a single nucleus. This leads to large nuclei and proportionately large cells. What are the benefits and costs of polyploidy?Polyploid cells occur in the liver, muscles, and maternal and extra-embryonic tissues, such as those that support placental development at the mother-fetus interface. Benefits include barrier tissue maintenance and repair after wounding. Wound repair involves polyploid cells becoming even larger to help cover the wound site. Also, having many copies of the genome supports rapid, efficient production of needed proteins, such as from placental genes that promote maternal milk production. However, there is not always a clear correlation between DNA copy number and actual protein output, and under experimental conditions some tissues seem to also function without being polyploid. Thus, investigation of additional tissue types is needed to better understand the hypothesized benefits of polyploidy.On the other hand, polyploidy also poses challenges to cells. In some cases, the entire cell's genome is not copied, but only DNA regions containing certain genes. This is an efficient way to support rapid production when only the specific proteins from those genes are needed. Yet, this partial increase in DNA copies is an unstable arrangement that usually triggers programmed cell death, known as apoptosis, as a form of biological quality control. Polyploid cells therefore require special genetic properties to suppress this. One key research system where this has been explored is the fruit fly Drosophila melanogaster, a powerful genetics model species. However, we discovered that critical genes for controlling programmed cell death, the so-called Grim Reaper genes, are a unique feature in flies. It remains unknown which genes serve this function in other animals. Also, one hallmark of cancer cells is that they have unstable DNA arrangements yet somehow evade programmed cell death. Research in new species on how polyploid cells handle the programmed cell death issue will identify critical genes and could help improve our understanding of genetics relevant to cancer treatment.In this research project, we will test the hypothesized benefits (barrier tissue structure, rapid protein production) and examine the potential risks (unstable DNA arrangement, need to block cell death) of polyploidy in a novel biological system: the two extra-embryonic tissues of the flour beetle Tribolium castaneum. These tissues serve epithelial barrier functions by surrounding and protecting the embryo. The serosa surrounds the embryo and yolk while the amnion, like its namesake in mammals, forms a fluid-filled, inner cavity. The serosa also has a rapid production role to make a cuticle layer that reinforces the eggshell. Notably, these tissues are stable and polyploid for most of their lifetime, and then they actively uncover the embryo and precisely undergo cell death. We have developed methods to investigate polyploidy in the beetle, including genome sequencing and live imaging microscopy that reveals healthy and experimentally perturbed barrier tissue structure. The serosa and amnion offer an excellent comparative system. Our preliminary work suggests that the serosa is capable of increased polyploidy to compensate in genetic models of wound-like tissue impairment while the amnion is not. This paves the way to better understanding of tissue-specific features of polyploidy and to uncover new critical genes involved in polyploidy control.