Research topics: Cell and molecular biology of segmentation and muscle development in Zebrafish
Research program: A Genetic, Genomic, and Cell Biological Analysis of Muscle Development in Zebrafish
I am interested in the molecular, genetic, and cellular basis of animal development. In particular, I wish to understand how both genetic and epigenetic events result in molecular signals that orchestrate the vast array of cell movements necessary to construct an organism. As a model system for the molecular and genetic control of morphogenesis, I take an interdisciplinary approach to analyzing muscle development in zebrafish embryos. Muscle formation during embryonic development is critical for normal locomotion and viability of all vertebrate animals. Not only has the zebrafish Danio rerio has become a prominent developmental genetics model system, but the zebrafish is also an excellent model system with which to study muscular dystrophy. Although many of the genes involved in muscular dystrophy are known, the fundamental cell biology of muscle formation and attachment is not yet understood. Treatment for this disease will require both gene identification and an intricate understanding of how genes function in a genetic and cell biological network. In zebrafish, like mouse, homologues of dystroglycan complex components are conserved and disruption in members of this complex, such as laminin, dystroglycan, and the zebrafish orthologue of the human Duchene muscular dystrophy gene, also cause a muscular dystrophy-like failure of muscle cells to either differentiate or maintain attachment to the extracellular matrix. Thus, there is good evidence that studies in the zebrafish embryo will significantly contribute to our understanding of the pathology of muscular dystrophy. In addition, recent evidence suggests that muscle regeneration may proceed via the same or similiar pathways as normal muscle development. Therefore, the study of muscle development may lead insights not only into congenital muscle disorders such as muscular dystrophy, but may also provide insights into muscle regeneration.
The specification and subsequent differentiation and morphogenesis of slow and fast twitch muscle fibers are crucial for normal muscle development and locomotion. In zebrafish, muscle is the major derivative of the embryonic somite, and slow and fast twitch muscle cells are spatially segregated very early in development. Slow muscle cells are initially the most medial muscle cells, but shortly after somite formation they undertake a dramatic lateral migration through the presumptive fast muscle domain to their final destination as the most superficial, or lateral, layer of muscle. Hedgehog signaling is known to be required for specification of slow muscle fibers in zebrafish. However, significantly less was known about the signals that promote development of fast muscle fibers, which constitute the vast majority of somitic cells. We have shown that when Hedgehog signaling is blocked, fast muscle cell elongation is disrupted. Using genetic mosaic analysis, we found that reception of the Hedgehog signal is required in slow muscle cells but not in fast muscle cells for fast muscle cell elongation. Furthermore, we found that slow muscle cells are sufficient to pattern the medial to lateral wave of fast muscle fiber morphogenesis even when fast muscle cells cannot perceive the Hedgehog signal. Thus, the medial to lateral migration of slow muscle fibers through the zebrafish somite creates a morphogenetic wave that patterns fast muscle fiber elongation in its wake. These results therefore demonstrate a novel mechanism of morphogenetic induction.
While these results have indicated that slow muscle fibers are sufficient for fast muscle fiber morphogenesis, it is not yet known how exactly this signal is transmitted. One of the immediate future directions of my lab is to study the cellular and molecular basis for fast muscle cell elongation.
Segmentation is a critical feature of development. The most obvious segmental structures in the vertebrate embryo are the somites: transient structures that give rise to vertebrae and much of the musculature. In zebrafish, the majority of somitic cells give rise to fast muscle fibers that are attached at either end to the somite boundary, also called the myoseptum. The myoseptum derives from the initial somite boundary and is analogous to the mammalian tendon in that it transduces force generated from muscle to the skeletal system. Despite the importance of proper myoseptum development for normal muscle development and function, the signals that regulate normal myoseptum development were not known. We have recently found that Hedgehog signaling is required for normal myoseptum development. This result gives us a springboard for further experiments that will address myoseptum development.
Image Description: Clarissa Henry