Cellular and Genetic Determinants that Establish and Diversify Proportion in the Vertebral Skeleton

项目摘要 脊椎骨骼是脊椎动物的一个定义特征，但人们对它是如何生长和发育知之甚少 不断进化。为了研究推动脊椎生长和比例的分子遗传过程，我们可以寻找 尾巴具有简单的几何形状和物种间极大的尺寸差异的脊椎。虽然人类 没有尾巴，许多哺乳动物用尾巴来攀爬、平衡和交流，因此进化了 不同长度的尾巴由不同数量的大小不等的椎骨组成。因此，尾巴是 高度进化，很可能代表了在整个轴向骨架中使用的模块化生长控制机制。 近缘啮齿动物尾巴多样性的一个例子是比较小鼠(小鼠)和 埃及跳鼠一种两足的小埃及跳鼠(雅各布跳鼠)，大约5000万只是从一个共同祖先进化而来的 几年前。除了后肢明显夸张之外，跳鼠还进化出了多种变化 脊椎骨骼支撑其直立姿势的脊椎骨骼，包括单个脊椎元素的伸长。这个 该应用的目的是确定小鼠脊椎生长的时间和细胞参数 和跳鼠，然后使用候选和公正的方法来研究分子机制， 这是脊椎生长速度差异的基础。我们假设基因表达和控制的局部变化 一块骨头比另一块骨头长得多或少的能力。这一假设将在追求三个方面得到检验 具体目标：1)定义建立和变化的椎体生长的时间和细胞参数 比例，2)揭示了利钠肽信号在驱动脊椎生长和不同伸长中的作用 以及，3)研究与不成比例的脊椎生长相关的基因表达差异。这些目标 将使用在我的实验室或通过合作建立的方法进行搜索，包括：MicroCT和 X射线成像和组织学、小鼠基因敲除线和RNA测序。这项拟议的研究需要 合理的实验方法在理解自然发生的椎体变异和 不同于在传统模型系统中观察到的表型，这些研究的意义 在于有机会打开一个相对未被探索的骨骼生物学领域，这将有助于我们 了解身体比例的发展和演变。

Project Summary The vertebral skeleton is a defining feature of vertebrates, yet little is known about how it grows and evolves. To investigate the molecular genetic processes driving vertebral growth and proportion, we can look to the tail with its vertebrae of simple geometry and extreme size differences between species. Although humans do not have tails, many mammals use their tails to climb, balance, and communicate and have therefore evolved tails of diverse lengths made up of different numbers of vertebrae with a range of sizes. The tail is therefore highly evolvable and likely represents mechanisms of modular growth control used throughout the axial skeleton. An example of tail diversity in closely related rodents is a comparison of the mouse (Mus musculus) and the bipedal lesser Egyptian jerboa (Jaculus jaculus), which diverged from a common ancestor about 50 million years ago. In addition to its more obviously exaggerated hindlimbs, the jerboa has evolved multiple changes to the vertebral skeleton to support its upright posture, including elongation of individual vertebral elements. The objective of this application is to define the temporal and cellular parameters of vertebral growth in mice and jerboas, then use candidate and unbiased approaches to investigate the molecular mechanisms that underlie vertebral growth rate differences. We hypothesize that local changes in gene expression and control the ability of one bone to grow more or less than another. This hypothesis will be tested in the pursuit of three specific aims: 1) Define the temporal and cellular parameters of vertebral growth that establishes and varies proportion, 2) Reveal the role of natriuretic peptide signaling to drive vertebral growth and differential elongation and, 3) Investigate gene expression differences associated with disproportionate vertebral growth. These aims will be pursed using methods that are established in my laboratory or by collaboration, including: microCT and X-ray imaging and histology, mouse knockout lines, and RNA sequencing. The proposed research takes advantage of sound experimental approaches to understand naturally occurring vertebral variation and phenotypes that are different from those observed in traditional model systems,The significance of these studies lies in an opportunity to open a relatively unexplored area of skeletal biology that will contribute to our understanding of body proportion development and evolution.