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Gabrielle Kardon

Assistant Professor of Human Genetics

B.S. Yale University

Ph.D. Duke University

Research

References

gkardon@genetics.utah.edu

 

Research

The vertebrate musculoskeletal system is essential for the support and movement of the body. To enable a wide variety of movements, the musculoskeleton is complex, consisting of more than 200 muscles attached via muscle connective tissue and tendons to bones. The proper development of the musculoskeleton requires the coordinated morphogenesis of muscle, muscle connective tissue, tendon, and skeleton. Our research, using the chick and mouse model systems, is aimed at elucidating the genetic and molecular mechanisms and tissue interactions necessary for patterning and assembling the musculoskeleton during vertebrate development. This research will both increase our understanding of normal musculoskeletal development and give us insights into the causes of human musculoskeletal diseases. Further comparative studies using a broad range of vertebrates are aimed at understanding musculoskeletal development in an evolutionary context and will allow us to identify key developmental innovations in the evolution of the vertebrate musculoskeleton.

Our initial research has focused on the development of the vertebrate limb musculoskeleton. With its accessibility to embryological and molecular manipulations, the vertebrate limb has been a classic system for studying morphogenesis. Much of this previous research has focused on skeletal morphogenesis, while relatively little is known about the development of the limb musculature. In bird and mammalian limbs there are over 40 muscles, with each muscle uniquely identifiable. During development, the limb muscle derives from migratory precursors originating from the somites, while the muscle connective tissue, tendons, and skeletal elements develop from the lateral plate mesodermal cells of the emerging limb bud. As the muscle precursors migrate into the limb they must differentiate into myofibers, become correctly patterned into distinct anatomical muscles, and be assembled with muscle connective tissue, tendons, and skeletal elements into a functional musculoskeletal system. To first establish when and where these migratory precursors are determined to become muscle cells and acquire patterning information, we conducted an extensive lineage analysis of single limb myogenic precursors in the chick. Surprisingly, we found that both muscle cell fate and patterning is determined by local extrinsic signals within the developing limb.

This lineage analysis, as well as other classical studies, suggested that signals from the limb mesoderm are important for patterning limb muscle. However, neither the molecular nature of the signal nor the exact tissue producing it was known. Recently, we have identified in both chick and mouse a population of limb mesodermal cells that expresses the transcription factor Tcf4, a downstream effector of the Wnt/ b -catenin signaling pathway, in a muscle-specific pattern independently of the muscle cells themselves. Using retroviral or adenoviral vectors in the chick to ectopically activate or disrupt the endogenous Wnt/ b -catenin/Tcf4 pathway, we determined that indeed this pathway in the limb mesodermal cells is critical for muscle patterning. The Tcf4 -expressing cells establish a prepattern in the limb mesoderm that determines where myogenic precursors differentiate and thus the basic pattern of limb muscles formed.

The discovery that Tcf4 -expressing limb mesodermal cells are critical for patterning limb muscle is an important starting point for our current investigations. Using both the chick and mouse model systems, we are studying 1. what regulates the spatiotemporal expression of Tcf4, critical for serving as a muscle prepattern and 2. how does Tcf4 expressed by limb mesodermal cells transduce a signal to nearby myogenic precursors. In addition, the Tcf4 -expressing mesodermal cells appear to be progenitors for muscle connective tissue, a tissue whose development is poorly known. We are currently examining the lineage of these cells. The identification of this early muscle connective tissue population by Tcf4, in combination with early markers of tendon and bone, will allow us to look for the first time at how the musculoskeletal system is assembled during development.

An additional interest in the lab is understanding how the developmental mechanisms controlling the limb musculoskeletal system have changed over evolutionary time. The evolution of the elaborate tetrapod limb musculoskeletal system from the relatively simple fin musculoskeleton has played a crucial role in the adaptive radiation of tetrapods. By comparing musculoskeletal development in a broad range of vertebrates, we endeavor to identify some of the key developmental innovations in the evolutionary transition of fins to limbs.

References