Defining the functions of CASK in skeletal muscle

Traditionally, the mammalian neuromuscular junction, the primary synapse found in skeletal muscle, has been termed the "simple synapse" for its basic chemical signaling mechanisms as compared to central nervous system synapses. However, recent data has suggested that the neuromuscular junction is far more complex than initially perceived and that various proteins are involved in the orchestration of synaptic function and development. One such protein, Ca2+/calmodulin associated serine/threonine kinase (CASK), has been previously identified as a key component in neuronal development. Our lab has found that CASK is concentrated at the neuromuscular junction, cytoplasm, and nuclei of skeletal muscle fibers, where evidence suggests that it may play a role in the structural scaffolding of synapses, receptor trafficking, protein phosphorylation, and transcription. To further elucidate the mechanisms of CASK in skeletal muscle, we have generated two distinct conditional knockout murine models of CASK in skeletal muscle. One model represents a knockout of non-synaptic CASK, while the other model represents a knockout of CASK in both the cytoplasm and at the neuromuscular junction. Recent data has shown that mice without CASK at the neuromuscular are not born at the predicted Mendelian ratios, while mice only deficient of cytoplasmic CASK show no observable phenotype. Further analyses of these models will be necessary to help to define the function of CASK in skeletal muscle. Studying the neuromuscular junction is the key to understanding the underlying mechanisms of neuromuscular diseases. Delineating the functions of CASK in skeletal muscle may lead to the identification of novel treatment approaches for neuromuscular diseases. Advisor: Jill Rafael-FortneyNo embarg