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

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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.