Ph.D., University of Washington, 1984
Genetics and cell biology; membrane trafficking and phosphoinositideMolecular and developmental biology of skeletal muscle; skeletal muscle regeneration and aging; skeletal muscle stem cells and gene therapy; growth factors and signal transduction.
The organization of the skeletal musculature requires precise regulation of cellular determination, migration, proliferation, differentiation, and patterning. These cellular events are thought to be mediated by extracellular factors. We are interested in elucidating the molecular mechanisms involved in skeletal muscle development. To identify and characterize extracellular regulators of skeletal muscle development, we use viral mediated gene transfer to alter gene expression in the developing chick limb. Basically, we either abrogate or augment signaling from a growth factor and assess the effects on skeletal muscle development. These studies have led to identification of FGFs as a regulator of muscle differentiation in vivo, TGF's as regulators of secondary myoblast proliferation and hedgehogs as regulators of myoblasts committed to make slow skeletal muscle fibers. We also are investigating the regulatory relationships between growth factors by inhibiting two pathways simultaneously. This is accomplished by infection with two distinct retroviruses. These methods are establishing epistatic relationships between growth factors. This type of information is critical to understanding and developing potential treatments for Muscular Dystrophies and muscle cachexia that occurs during disease, injury, and aging.
We are characterizing skeletal muscle stem cells and comparing these with skeletal muscle satellite cells, the cells that regenerate injured skeletal muscle tissue. Loss of muscle regeneration is thought to be causative for Muscular Dystrophies, cachexia following severe illness, or injury and aging. Our goals are to understand the behavior of these two types of cells and their respective potential contributions to skeletal muscle regeneration. We utilize mouse genetics, a myofiber organ culture system and satellite cell lines to examine the function of satellite cells and stem cells in environments where specific growth factor signaling pathways have been abrogated or augmented. To study these pathways we use mouse genetics, where we are examining mice harboring null alleles or conditional null alleles; and infection of muscle tissue or myofibers with recombinant adenoviruses or retroviruses. Presently, we are investigating the roles of FGF, TGF___hepatocyte growth factor, and insulin-like growth factor in muscle regeneration. Our longterm goals are to understand growth and differentiation of skeletal muscle satellite and stem cells for eventual use in cellbased gene therapy approaches.
Skeletal Muscle Satellite Cells
The bright fluorescent cells mark satellite cells on an intact muscle fiber that have undergone one cell doubling since the fiber was explanted. The lighter fluoresence marks all myofiber cell nuclei. The majority of nuclei belong to the muscle fiber.
Oncogenic Ras-induced proliferation requires autocrine fibroblast growth factor 2 signaling in skeletal muscle cells.
Fedorov, YV, Rosenthal, RS, and Olwin, BB J Cell Biol, 152(6):1301-5. 2001
ERK1/2 is required for myoblast proliferation but is dispensable for muscle gene expression and cell fusion.
Jones, NC, Fedorov, YV, Rosenthal, RS, and Olwin, BB J Cell Physiol, 186(1):104-15. 2001
MyoD(-/-) satellite cells in single-fiber culture are differentiation defective and MRF4 deficient.
Cornelison, DD, Olwin, BB, Rudnicki, MA, and Wold, BJ Dev Biol, 224(2):122-37. 2000
Loss of FGF receptor 1 signaling reduces skeletal muscle mass and disrupts myofiber organization in the developing limb.
Flanagan-Steet, H, Hannon, K, McAvoy, MJ, Hullinger, R, and Olwin, BB Dev Biol, 218(1):21-37. 2000
Regulation of myogenesis by fibroblast growth factors requires beta-gamma subunits of pertussis toxin-sensitive G proteins.
Fedorov, YV, Jones, NC, and Olwin, BB Mol Cell Biol, 18(10):5780-7. 1998