Basement Membranes: Structure and Function in Development, Regeneration, and Cancer

Our research centers on the role of extracellular matrix in cell differentiation. The current focus is on development and regeneration of muscle and nerve. Muscle normally has a large capacity for regeneration, which involves activation and proliferation of muscle stem cells and their differentiation into functional muscle fibers. Muscular dystrophy is a group of rare genetic diseases characterized by degeneration and loss of function of skeletal muscle. Thus, in muscular dystrophy and other muscle diseases, and even in normal aging, regeneration is insufficient to compensate for degeneration. Our hypothesis is that the proteins mutated in the muscular dystrophies are among the ones most critical for regeneration. We have generated a mouse model for merosin (laminin alpha -2)-deficient congenital muscular dystrophy by ablating the lama2 gene through the insertion of a reporter gene, lacZ. Homozygous mutant mice develop an early, lethal form of muscular dystrophy. By monitoring b-galactosidase activity during muscle development and regeneration, we determined that the lama2 gene was active in mononucleated myoblasts but inactive in the differentiated, multinucleated myotubes. In contrast, the protein is deposited around the myotubes. Stem cells are activated and proliferate in the absence of laminin alpha -2, but very few myotubes form,. The myotubes that do form can not complete maturation into functional muscle. We conclude that laminin alpha -2 is most essential for late stages of muscle regeneration. Additional factors are important for regeneration of striated muscle, including stem cells. We currently study the muscle-specific sarcoglycan genes as well as the muscle specific caveolin, caveolin-3. Sarcoglycans and caveolin-3 are mutated in particular forms of limb-girdle muscular dystrophy. In collaboration with Drs. Millan and Stallcup, we aim to identify mesenchymal stem cells that may be recruited and used as an alternative source of cells for muscle regeneration in situations where the resident stem cell pool in muscle has been depleted.