REGULATION OF MEF2 TRANSCRIPTION FACTORS DURING SKELETAL MUSCLE DEVELOPMENT

Throughout pre- and post-natal development, skeletal muscle forms in a very complex and asynchronous fashion, which involves different cell populations and different intra- and extra-cellular controls, which ensure the formation of different generations of muscle fibers in a correct spatio-temporal context. The first differentiated muscle cells can be observed very early, in embryological strctures known as myotomes. Few days later primary fibers will form, both in the trunk and in the limb, each surrounded by a population of proliferating cells known as secondary or fetal myoblasts. Only during the fetal stage of development, fetal myoblasts will fuse with each other, but not with pre-existing primary fibers, to form secondary fibers. These are initially smaller than primary fibers but, during later development, they reach the size of primary fibers and, at birth, the number of skeletal muscle fibers of a mammal is fixed and will not change unless degeneration-regeneration occurs. Primary fibers, as well as secondary fibers, express initially specific subsets of proteins. With further development, both fibers begin to express “neonatal” and then “adult” subsets of proteins. This complex picture likely depends on two separate but interacting mechanisms of control: 1) a differential sensitivity of embryonic and fetal myoblasts to extracellular signals present in the microenvironment; 2) an autonomous cell differentiation program, which acts in different populations of myoblasts. Our research focuses on the understanding of the second mechanism of control. In particular we believe that the regulation of the activity of a specific protein called Myocyte Enhancer binding Factor 2 (MEF2) plays a crucial role in the activation of the fetal muscle genetic program. We also believe that the understanding of the genetic regulatory mechanisms might shed light on the pathogenesis of a group of diseases known as Benign Childhood Myopathies.