The fundamental question that drives my research is: " How a single cell, the fertilized egg, develops into an animal with thousands of distinct type of cells - muscle cells, neurons, epidermal cells, blood cells, and so on?" We are particularly interested in the cellular and molecular mechanisms that control the differentiation of muscle and skeletal cells during embryogenesis. Specifically, we use zebrafish as a model system to investigate the role of growth factors and their downstream transcriptional factors in the formation and differentiation of vertebrate skeletal and muscle cells during embryogenesis.

Skeletal muscle and bone are specialized tissues that make up the muscle/skeletal system that confers multiple mechanical and biological functions, such as providing physical support for our body, protecting vital organs (e.g., brain, lung). The important function of muscle/skeletal system can be easily recognized in day-to-day life, where millions of people suffer from muscular and skeletal diseases such as muscular dystrophy, or osteoporosis. The better understanding of the regulation of muscle and bone formation during embryogenesis will provide new insights into the molecular mechanisms of muscle/skeletal diseases and give rise to novel strategies for new drug design as well as alternative therapeutic approach using embryonic stem cells.

Many important insights into muscle and bone formation have come from studies of animal models, such as mice, chick, and fish. These studies have provided fundamental information about genes that regulate the development of bone and muscle cells. It is apparent that most of the genes or genetic pathways that control muscle or skeleton formation are highly conserved in vertebrates, and signaling molecules required for embryonic muscle/skeletal development are also important in adulthood. Therefore, in recent years there has been an increasing interest in the search for new genes involved in bone and muscle development in animal model systems. Zebrafish have become an important model for developmental studies, having several advantages compared with other model systems. In particular are the easy accessibility of zebrafish embryos for direct observation of their development and their suitability for systematic mutagenesis studies to identify genes regulating the development of various tissues and organs, including the muscle/skeletal system.

The research objective of my laboratory is to use zebrafish as a model system to identify the genetic program involved in muscle and skeleton formation. Our research focuses on the role of growth factors and their downstream transcription factors in the formation of vertebrate muscle and skeleton during embryogenesis. We discovered that the differentiation of muscle fibers is regulated by signals from their neighboring tissues. We found that growth factor Hedgehog protein, secreted by notochord cells, played an important positive role in specifying slow muscles. Overexpression of Hedgehog protein in zebrafish embryos (using transgenic technology) induced the formation of extra slow muscle cells, and at the same time blocked the formation of fast muscle cells. Mutation of Hedgehog protein or its downstream gene, named Gli2, blocked the development of slow muscle cells. In addition, we demonstrated that the development of muscles is controlled by both positive and negative regulators. BMP (bone morphogenetic protein), another type of growth factor, acts as the negative regulator in slow muscle formation. Moreover, we discovered that BMP also inhibits bone development in fish embryos.

Results from these studies have potential application in clinical research and aquaculture, because knowledge gained from these studies may lead to design of new drugs that could regulate the activities of these growth factors for treatment of muscular and skeletal diseases, and new strategies to instruct differentiation of ES cells specifically into muscle or skeletal cells for cell based therapy. Moreover, these studies may lead to new approaches to enhance muscle growth for seafood production in aquaculture.