Mechanisms of Developmental Fidelity

 描述(申请人提供)：发育中的胚胎面临大量并行和顺序的决定，每个决定都面临着波动的环境和分子“噪音”，因此充满了一定的错误率。虽然纠正决策错误的质量控制系统肯定是无处不在的，对人类发展至关重要，但人们对它们几乎一无所知。推动这项研究的假设是，存在在发育过程中运行的质量控制系统，这些系统确保高保真结果，并且这些系统可能在不同的发育过程中发挥作用。我们将利用线虫高度可复制的发育来研究调节发育保真度的机制。我们发现，雄性线虫在尾射线感官结构形成过程中的程序性细胞死亡(PCD)的激活和主要器官的左右(L/R)方向上经常出现错误，并且这些错误的倾向在不同的野生菌株(同型)之间存在很大差异。在这两个过程中错误率高的同种类型(“低保真”品系)在其他过程中也表现出很大的差异，包括生殖系干细胞增殖和L1幼虫长度。相反，在前一种性状中错误率较低(“高保真”)的品系，在后一种性状中也表现出较低的方差。我们打算通过两个目的来揭示随机PCD的分子遗传学基础和L/R惯用手的错误，并研究不同发育过程的保真度是否可能受到共同机制的影响。在目标1中，我们将通过分析97个不同的发育过程中的误差，以及从高保真度和低保真度衍生的重组自交系(RIL)，来研究保真度的变异在几个发育过程中是完全独立的还是显著的协变。我们将评估忠诚度是否会对其他功能产生影响，包括增长和长寿。在目标2中，我们将确定PCD和L/R器官利手等事件中发育错误/保真度变异的分子遗传学基础。虽然所建议的研究的高风险/高收益方面使它们适合于R21机制，但无论保真度控制机制的一般性如何，都将获得与PCD的随机性和L/R器官不对称的调节失调相关的重要结果。拟议中的研究有望提供有关出生缺陷和细胞增殖失调(包括癌症)的潜在调控机制的新信息。此外，揭示导致不适当的随机细胞死亡的机制可能为神经退行性疾病中的零星细胞死亡提供重要的见解。

 DESCRIPTION (provided by applicant): Developing embryos face vast numbers of parallel and sequential decisions each that is confronted with fluctuating environments and molecular "noise," and is thus fraught with a certain rate of error. While quality control systems that corret decision-making errors must be pervasive and are critical for human development, almost nothing is known about them. The hypothesis driving the proposed studies is that there exist quality control systems operating during development that ensure high-fidelity outcomes and that such systems may function across disparate developmental processes. We will avail of the highly reproducible development of C. elegans to investigate the mechanisms that regulate developmental fidelity. We found that C. elegans males show frequent "errors" in the activation of programmed cell death (PCD) during formation of the tail ray sensory structures and in the left-right (L/R) orientation of the major organs and that the propensity for these errors differs widely between different wild isolates (isotypes). Isotypes with high error rates in these two processes ("low-fidelity" strains) also show high variance in other processes, including germline stem cell proliferation and L1 larval length. In contrast, a strain with low error rates ("high-fidelity") in the former traits also shows low variance in the latter. We propose to unveil the molecular genetic basis for stochastic PCD and errors in L/R handedness and to investigate whether the fidelity of different developmental processes might be influenced by common mechanisms, through two aims. In Aim 1, we will investigate whether variation in fidelity is fully independent or significantly co-varies across several developmental processes by analyzing errors in disparate developmental processes across 97 isotypes and recombinant inbred lines (RILs) derived from "high-" and "low-fidelity" isotypes. We will evaluate whether fidelity has an impact on other functions including growth and longevity. In Aim 2, we will identify the molecular genetic basis for variation in developmental errors/fidelity in PCD and L/R organ handedness and other events. While the high-risk/high-gain aspect of the proposed studies make them appropriate for the R21 mechanism, important results relevant to stochasticity of PCD and dysregulation of L/R organ asymmetry will be obtained regardless of the generality of fidelity-controlling mechanisms. The proposed studies promise to yield new information regarding regulatory mechanisms underlying birth defects and dysregulation of cell proliferation, including in cancer. In addition, uncovering mechanisms that lead to inappropriate, stochastic cell death may provide important insights into sporadic cell death in neurodegenerative diseases.