Clarissa Henry, Ph.D.
University of Maine
Dystroglycanopathies are neuromuscular diseases that result in progressive muscle wasting, which decreases quality of life and often leads to early death. Dystroglycanopathies result from mutations in genes that encode proteins that participate in dystroglycan (DG) glycosylation. DG is a transmembrane receptor for extracellular matrix (ECM) proteins and its glycosylation is necessary for cells to adhere to their surrounding ECM at both neuromuscular junctions (NMJs) and myotendinous junctions (MTJs). The contribution of disrupted cell-ECM adhesion to altered structure and function of the neuromuscular system in the context of dystroglycanopathies is poorly understood. This is partially because dystroglycanopathies caused by the same genetic mutation have variable clinical presentation, including severe congenital onset muscular dystrophy with eye/brain involvement, congenital myasthenic syndrome, and milder adult-onset limb girdle muscular dystrophies. There are multiple roadblocks to understanding the phenotypic variation of these incurable diseases. The neuromuscular system involves coordinated development of neural and muscle tissues to form NMJs, but mechanisms are not fully understood. The effects of disrupted primary motor neuron development on subsequently developing secondary motor neurons, muscle, and NMJ structure and function are not understood in the context of muscular dystrophies such as the dystroglycanopathies. A genetic model of dystroglycanopathies in a vertebrate model that allows longitudinal studies of neuromuscular development is needed to address these gaps. We generated a zebrafish model of gmppb-associated dystroglycanopathy. Our preliminary data suggest that gmppb is required for primary motoneuron, NMJ, and muscle development and/or homeostasis. Gmppb mutant zebrafish exhibit mild or severe phenotypes that can be quantitatively segregated based on birefringence (an indicator of skeletal muscle structure) at 2dpf. The development of skeletal muscle and myotendinous junctions are disrupted (to different extents) in both mild and severe mutants. Longitudinal studies indicate that mild embryos remain mild through early larval stages (7 days). Remarkably, half of the severe embryos improve and exhibit a mild phenotype at 7 days. These data indicate that compensatory mechanisms mediate a switch from severe to mild phenotypes. Thus, gmppb mutants are a promising model with which to study the basic mechanisms underlying musculoskeletal development, homeostasis, and plasticity and I will discuss our current progress towards these goals.
Support for this seminar is provided by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103423.