Developmental Genetics and the Evolution of Tendon Growth

Abstract

Hominoids are characterized by a high degree of variation in Achilles tendon size, and a tendon’s capacity for energy storage is directly related to its relative size. Thus, it has been hypothesized that the relatively long, thin human Achilles tendon is an adaptation to decrease the cost of bipedal locomotion, especially during running. However, there is poor understanding of the mechanisms involved in tendon growth and how these processes lead to differences in adult tendon size among different organisms. Using a mouse model, this dissertation characterizes the transcriptomic and regulatory mechanisms that control the postnatal growth of limb tendons to better understand the process of tendon size evolution. Chapter Two introduces the concept of tissue growth in the context of tendon biology, hominin evolution, and human locomotion. Chapter Three examines the changing proliferative potential of tendon cells during the six weeks immediately following birth. We also characterize expression profiles of known target genes and show that mouse tendon growth occurs in two general phases: proliferative growth and increased matrix production. Chapter Four establishes a comprehensive transcriptomic profile of tendon and presents an open chromatin assay to identify putative regulatory elements involved in the transcriptional regulation of these growth-related genes. These studies reveal the complex gene interactions that coordinate growth and may drive the observed shift in cell phenotype. Lastly, Chapter Five provides a rich data set for the discovery of *cis*-regulatory modules and demonstrates how these putative regulatory modules can be used to address questions about the evolution of Achilles tendon growth in primates in order to contextualize our findings in mice within a human evolutionary framework.