Research Topics
Department of Cell and Structural Biology and College of Medicine
Ph.D. (1971) University of Colorado
Research Topics
Research Interests
General: The a7b1 integrin is a laminin receptor on the surface of skeletal myoblasts and muscle fibers. For a review, see Burkin and Kaufman, Cell and Tissue Research 296:183-190, 1999. Our research focuses on the roles of this integrin in:
Background: We previously used monoclonal antibodies to study developmental changes in the myoblast membrane. Our analyses of single myogenic cells demonstrated that a dynamic remodeling of the cell membrane is part of the biochemical and morphologic differentiation of skeletal muscle. We became particularly interested in one membrane glycoprotein because it was selectively expressed in skeletal and cardiac muscle and because it was developmentally regulated during differentiation. We cloned and sequenced the gene that encodes this protein and thereby identified it as a novel integrin alpha chain which is now referred to as a7 integrin. In association with the b1 integrin chain, the a7b1 complex serves as a receptor for the extracellular matrix protein laminin.
Role of the a7b1 integrin in muscle development: The a7 integrin gene is regulated during development of the myogenic lineage and the molecular mechanisms that underlie this are now being studied. In addition, there are at least three distinct a7 cytoplasmic domains and two distinct extracellular domains of the protein that arise by developmentally-regulated alternative splicing. During development, the a7b1 integrin maintains proliferation of muscle precursor cells as well as their mobility. Thus, this integrin functions to expand the population of myogenic precursor cells as well as getting them to sites of muscle fiber formation. Studies of additional functions of the a7b1 integrin, via its use of alternative cytoplasmic and extracellular domains during skeletal muscle differentiation are underway. In developed muscle, the a7b1 integrin is localized at the periphery of muscle fibers and it is also concentrated at myotendinous and neuromuscular junctions. Different isoforms of the integrin localize to these different sites. We are now studying the mechanism that underlies this site-specific localization.
Role of the a7b1 integrin in the integrity of normal and dystrophic muscle in humans and mice: The a7b1 integrin appears to be both directly and indirectly causally related to several neuromuscular diseases (J. Cell Science 110:2873-2881, 1997). Increased expression of a7b1-mediated linkage of fibers and the extracellular matrix is seen in Duchenne muscular dystrophy and this may compensate for the absence of the dystrophin-mediated linkage. We are using transgenic animals to determine whether overexpression of this integrin can strengthen dystrophic muscles and ameliorate the development of muscle pathology. In contrast, down-regulation of expression of the integrin contributes to the development of pathology in congenital laminin-deficiencies. Furthermore, mutations in the a7 integrin gene underlie additional congenital neuromuscular diseases (Nature Genetics 19:94-97, 1998). The functional roles of this integrin in the formation and stability of neuromuscular and myotendinous junctions and its localization between fibers suggest that altered expression or function of this integrin may a have widespread involvement in other neuromyopathies. Experiments are in progress to determine this.
Enhanced expression of the a7b1 integrin inhibits development of muscular dystrophy and restores longevity. The defective association of skeletal and cardiac muscle with their surrounding basal lamina underlies the pathologies associated with a variety of congenital and acquired muscular dystrophies and cardiomyopathies. Two major mechanisms by which fibers attach to laminin in the basal lamina are the dystrophin glycoprotein complex and the a7b1 integrin. Duchenne muscular dystrophy, a2 laminin congenital muscular dystrophy, sarcoglycan related muscular dystrophy, and a7 integrin congenital muscular dystrophy result when one of those linkage systems is defective. Expression of the a7b1 integrin linkage system is enhanced in Duchenne patients and in mdx mice and both have mutations in their dystrophin gene. This suggested that the integrin may compensate, in part, for the absence of the dystrophin glycoprotein complex. To test this hypothesis we have over-expressed the a7 integrin chain in mdx/utrophin (-/-) mice. We have found that the transgenic expression of the a7 integrin chain in these mice ameliorates development of disease and maintains longevity in animals that would otherwise develop severe myopathy and die. This suggests that bolstering the integrin-mediated association of muscle with the extracellular matrix may prevent not only Duchenne muscular dystrophy, but also other muscle diseases that arise due to additional defects in the dystrophin glycoprotein complex (manuscript submitted).
The a7b1 integrin in the formation of neuromuscular junctions - molecular mechanisms and signal transduction: We recently discovered that specific isoforms of the a7b1 integrin play a functional role in the formation of neuromuscular junctions (J. Cell Biology 143:1067-1076, 1998; J. Cell Science 113:2877-2886, 2000). We are currently studying the physiologic and signal transduction mechanism mediated by this integrin during formation of neuromuscular junctions. Based on the involvement of the a7b1 integrin in the formation and integrity of neuromuscular junctions, mutations in the a7 integrin might be expected to underlie muscle diseases that exhibit a neurologic component. In this regard, we have recently identified three patients with mutations in the a7 gene that do not express the a7 protein and who show congenital myopathies with delayed motor milestones. We are pursue these exciting studies as well.
Current Research Funding
NIH, Muscular Dystrophy Association of American