Spatial Dynamics of Tissue and Organ Size Control

 产品说明： 组织和器官的大小是非常精确的，我们注意到双侧结构（如四肢）的对称性，以及遗传相同的个体彼此相似的程度。组织和器官不仅达到特定的大小，而且在细胞死亡或细胞周期动力学改变的情况下也是如此， 提出了反馈控制机制。我们小组关于持续更新组织的工作已经确定了一种通用的“积分负反馈”策略，由此干细胞或祖细胞更新的负调节自动实现鲁棒的设定点控制。这种反馈可能是通过扩散性生长因子来传达的--正如我们和其他人在嗅上皮（OE）、视网膜和肌肉中所展示的那样--但各种分子和机制也可以发挥类似的作用。然而，不管机制如何，局部反馈控制增殖的能力 受到距离限制：分子和机械信号在特征长度尺度上衰减。这样的尺度通常很短（大约100微米或更小），这一事实引发了一个问题：局部反馈如何可能控制比其大三四个数量级的组织和器官的尺寸。 在这里，我们通过数学建模和动物实验相结合来解决这个问题。初步建模已经确定了几种策略，原则上可以通过以下方式控制大尺寸 短程反馈这些策略利用了这样一个事实，即控制发育组织和器官的生长不是一个“稳态”问题，而是一个控制自我终止轨迹的问题。 通过考虑各种可能的细胞谱系关系和反馈相互作用的类型-所有这些都是由实际开发系统中的观察所激发的-我们将使用建模和模拟来系统地发现设计原则，其中可以构建大型组织和器官的反馈控制策略。随后，我们将计算测试的假设，实验区分不同的潜在的生长控制策略的最佳方法是通过瞬时消融特定谱系阶段的细胞的定义比例，并观察最终组织大小的后果。最后， 我们将进行这样的瞬时细胞消融来研究小鼠中三种神经结构-嗅上皮、神经视网膜和大脑新皮质的发育，目的是确定这些组织用于不同尺寸的大小控制的策略。这项工作将提供对发育基本过程的基本见解，以及对神经系统大小控制的具体见解。研究结果将直接关系到小头畸形和其他出生缺陷的病因，以及发育迟缓、追赶性生长和生长不对称的临床现象。

 DESCRIPTION: The sizes of tissues and organs are specified with great precision, a fact we notice in the symmetry of bilateral structures (such as limbs), and the degree to which genetically identical individuals resemble each other. Not only do tissues and organs reach specific sizes, they do so in the face of cell killing or alterations to cell cycle kinetics, which suggests a feedback control mechanism. Work from our group on continually- renewing tissues has identified a general "integral negative feedback" strategy, whereby negative regulation of stem or progenitor cell renewal automatically achieves robust set-point control. Such feedback may be conveyed by diffusible growth factors-as we and others showed in the olfactory epithelium (OE), retina, and muscle-but a variety of molecules and mechanisms could act similarly. Regardless of mechanism, however, the ability of local feedback to control proliferation is subject to distance limitations: molecular and mechanical signals decay over characteristic length scales. The fact that such scales are often very short-on the order of 100 µm or less-raises questions about how local feedback could possibly control the sizes of tissues and organs that are three or four orders of magnitude larger. Here we address this issue through a combination of mathematical modeling and animal experimentation. Preliminary modeling has identified several strategies that could, in principle, enable large sizes to be controlled through short-range feedback. These strategies exploit the fact that controlling developmental tissue and organ growth is not a "steady-state" problem, but one of controlling a self-terminating trajectory. By considering a variety of possible cell lineage relationships and types of feedback interactions-all of which are motivated by observations in actual developing systems-we will use modeling and simulation to systematically discover the design principles out of which strategies for feedback control of large tissues and organs may be constructed. Subsequently, we will computationally test the hypothesis that the best way to distinguish experimentally among different potential growth-control strategies is by transiently ablating defined proportions of cells at specific lineage stages, and observing the consequences for final tissue size. Finally, we will perform just such transient cell ablations to investigate the development of three neural structures-the olfactory epithelium, the neural retina, and the cerebral neocortex-in mice, with the goal of identifying the strategies these tissues use for size control in different dimensions. This work will provide both basic insights into fundamental processes of development, and specific insights into size control in the nervous system. The results will be of direct relevance o the etiology of microcephaly and other birth defects, as well as to clinical phenomena of stunting, catch-up growth, and growth-asymmetry.