The impact of aneuploidy on neuronal cell behavior

描述（由申请人提供）：非整倍体是基因组中染色体数量异常的状态。虽然非整倍体通常与癌症和神经变性等疾病有关，但最近的研究也表明，非整倍体是一种大效应突变，可以产生巨大的表型变异，使细胞能够迅速适应环境压力。有趣的是，据报道，频繁的非整倍体与某些正常体细胞有关，如肝细胞、神经元和神经干细胞。本R21研究的目的是探索非整倍性可能是神经元行为多样性的遗传机制。具体来说，我们将使用小鼠神经干细胞（NSCs）的体外培养和分化作为实验模型，以首次了解非整倍性如何影响神经细胞的生长和分化，以及可能的潜在机制（例如，通过核型介导的转录组和蛋白质组的变化）。根据最近对单细胞生物的研究，我们还将调查神经非整倍体是否可能由应激诱导和/或提供表型变异，从而使脑细胞能够进化适应应激条件。为了支持所提出的实验，我们已经建立了一个有效的管道来产生和分离具有同质或异质核型的非整倍体NSCs，并建立了几种定量染色体数量和单个或群体细胞核型的方法。我们提出的研究有可能揭示神经元复杂性背后可能的遗传机制。所获得的知识可以促进对染色体数目异常引起的脑部疾病发病机制的理解。

DESCRIPTION (provided by applicant): Aneuploidy is the state of having an abnormal number of chromosomes in the genome. Although aneuploidy is often associated with diseases such as cancer and neural degeneration, recent studies have also demonstrated aneuploidy to be a large-effect mutation that could produce dramatic phenotypic variation and enable cells to rapidly adapt to environmental stress. Intriguingly, frequent aneuploidy has been reported to associate with certain normal somatic cells, such as liver hepatocytes and neurons and neural stem cells. The goal of this R21 study is to explore the idea that aneuploidy may be a genetic mechanism contributing to behavioral diversity of neurons. Specifically, we will use in vitro culture and differentiation of mouse neural stem cells (NSCs) as the experimental model to gain a first insight into how aneuploidy impacts the neuronal cell growth and differentiation and what might be the underlying mechanism (e.g. via karyotype-mediated changes in the transcriptome and proteome). We will also investigate, in light of recent studies in unicellular organisms, whether neuronal aneuploidy may be induced by stress and/or provide phenotypic variation that enable evolutionary adaptation to stress conditions encountered by brain cells. Supporting the proposed experiments, we have developed an effective pipeline for the generation and isolation of aneuploid NSCs with homogeneous or heterogeneous karyotypes and established several methods for quantifying chromosome number and karyotyping of single or populations of cells. Our proposed study has the potential to shed light on the possible genetic mechanisms underlying neuronal complexity. The knowledge gained could advance the understanding of pathogenesis of brain disorders due to chromosome numerical abnormalities.