The impact of aneuploidy on neuronal cell behavior

描述（由申请人提供）：非整倍性是基因组中染色体数目异常的状态。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，可以产生显着的表型变异，使细胞能够快速适应环境压力。有趣的是，频繁的非整倍体已被报道与某些正常的体细胞，如肝细胞和神经元和神经干细胞。这项R21研究的目的是探索非整倍体可能是导致神经元行为多样性的遗传机制。具体来说，我们将使用体外培养和分化的小鼠神经干细胞（NSC）作为实验模型，以获得第一次洞察非整倍性如何影响神经元细胞的生长和分化，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）。我们还将调查，根据最近的研究，在单细胞生物，神经元非整倍性是否可以诱导应激和/或提供表型变异，使进化适应脑细胞遇到的压力条件。支持所提出的实验，我们已经开发了一个有效的管道，用于产生和分离具有同质或异质核型的非整倍体神经干细胞，并建立了几种方法，用于定量染色体数目和核型分析的单个或群体的细胞。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由于染色体数目异常导致的脑疾病的发病机制的理解。

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.