Mouse genetic models to understand human musculoskeletal disease

Myosins are proteins which are present in all cell types, essential for fundamental cellular functions such as cell movement, cell division and transport of cargoes within cells. A specialized set of myosin proteins known as muscle myosins are expressed by the skeletal muscle, which are required for muscle contraction. While most muscle myosin proteins are expressed in the adult muscle, two are expressed only during embryonic development. Very little is known about these developmentally expressed muscle myosins except that mutations in the gene encoding one of the myosins, MYH3, leads to Freeman-Sheldon Syndrome (FSS) in humans, a genetic disease causing severe musculoskeletal abnormalities including joint deformities, bent fingers, club feet, curved spine and facial anomalies. FSS patients have compromised movement, respiratory, speech and feeding problems and delayed growth and development.

In recent work from our laboratory, we have used the laboratory mouse to understand the functions of the Myh3 gene (which codes for MyHC-embryonic protein) during embryonic, fetal and neonatal development. We generated targeted mouse models for Myh3 using which we made the following four discoveries. First, we find that loss of MyHC-embryonic leads to muscle abnormalities including alterations in muscle fiber type, fiber number and fiber size. Second, we find that MyHC-embryonic is required to regulate the rate of differentiation of the muscle stem cells during development, and this effect is mediated by fibroblast growth factor (FGF) signaling. Third, although MyHC-embryonic is expressed in all muscles, we find that loss of MyHC-embryonic has differential effects on distinct muscles. Fourth, adult mice lacking MyHC-embryonic exhibit scoliosis (abnormal curved spine), an abnormality seen in individuals with Freeman-Sheldon Syndrome.

Thus, using targeted mouse models, we have characterized the function of MyHC-embryonic and developmental myosins in general, during embryonic stages of development. Loss of function of MyHC-embryonic leads to scoliosis in adult mice, a defect seen in FSS patients, and this mouse model could thus be a valuable tool in understanding the defects underlying this congenital disorder.

In the future, we would like to understand how myosin function is important for adult muscle function. Muscle has a resident population of stem cells which are required for regeneration of the muscle following injury and disease. Using the mouse models that we have generated, we would like to investigate the function of myosin protein in muscle stem cell mediated regeneration following injury or disease. We are also interested in understanding how mutations in myosin  leads to genetic diseases such as Freeman-Sheldon Syndrome. In the long term, these studies should shed light on how myosins contribute to muscle stem cell function, regeneration and muscle disease, which should help develop new strategies to treat muscle injury and disease.

For full article: doi: 10.1242/dev.184507


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