“The Role of a Novel Pathway in Vertebrate Tendon Development”

Key Words: Tendon formation, Musculoskeletal development, Congenital skeletal disorders and contractures

Tendons provide the connections between your muscles and bones and enable coordinated movement. Defects in their development can result in contractures and clubfoot, congenital abnormalities in which tendons and skeletal structures are malformed causing restricted movement. Treatments for children with these conditions involve multiple surgeries and extensive physical therapy. Although the primary underlying causes of these conditions are unknown, they are thought to be multifactorial and involve the aberrant development of the connective tissues. Therefore, comprehensive knowledge of the molecular pathways that guide tendon development would have broad impact in our understanding of the etiology of these types of congenital defects. Surprisingly, we understand very little about the induction and development of tendon progenitor cells.

To address this gap in our knowledge, we are using the zebrafish model system to discover new pathways that affect early tendon formation. We have shown that zebrafish and mammalian tendons are similar in gene expression, developmental regulation, and ultrastructural properties, making them an excellent system for studying tendon biology. Previous screening efforts identified a new pathway to have an important role in regulating tendon progenitor cells in the developing zebrafish embryo. Inhibition of this pathway caused a significant expansion of tendon markers in zebrafish and mouse systems, demonstrating conservation of activity across vertebrates. This unique phenotype will allow us to dissect the pathways regulating tendon cell populations during musculoskeletal development. We propose to elucidate the mechanisms underlying the expansion of tendon tissues using molecular and genetic assays in the zebrafish. We propose that by understanding how this pathway regulates tendon progenitor cell numbers, we will gain valuable mechanistic insight into tendon developmental mechanisms. Knowledge of these processes will further impact our understanding of congenital musculoskeletal abnormalities.