The Role of the Actin Regulator Cyclase-associated Protein 2 (CAP2) for Mammalian Skeletal Muscle Development.
Actin is a structural protein that is a major component of the eukaryotic cytoskeleton. It is not only important for morphology and stability of cells, but also for dynamic processes such as cell migration, adhesion, growth or contraction. In muscle cells, the highly structured complex of myosin and...
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|Actin is a structural protein that is a major component of the eukaryotic cytoskeleton. It is not only important for morphology and stability of cells, but also for dynamic processes such as cell migration, adhesion, growth or contraction. In muscle cells, the highly structured complex of myosin and actin filaments is essential for the coordinated contraction of muscle fibers, which ultimately generates muscle strength. In order to achieve this function, actin filaments have to build up and rebuilt dynamically during muscle development. However, the molecular mechanisms involved are still largely unknown. The need to elucidate these mechanisms arises from the finding that a large number of human myopathies are associated with defects in the actin cytoskeleton. Previous studies identified the transcription factor SRF (serum response factor) as a major regulator of skeletal muscle development in humans and mice. In a feedback mechanism, SRF is activated in an actin-dependent manner and in turn controls the expression of actin and actin-regulatory proteins. One of the main activators of SRF is MRTF (myocardin related transcription factor), which can be sequestered by actin monomers, thus preventing translocation and subsequent activation of SRF in the nucleus. This cumulative dissertation presents two studies that aim to elucidate the underlying processes of myopathies during skeletal muscle development. In the first publication, "CAP2 deficiency delays myofibril actin cytoskeleton differentiation and disturbs skeletal muscle architecture and function", we identified a previously unknown function for the actin-regulatory protein CAP2 (cyclase-associated protein 2) during skeletal muscle development in mammals. We showed that CAP2 controls the remodeling of actin filaments in developing skeletal muscle and is therefore essential for the differentiation of muscle fibers. As a consequence of CAP2 loss, mouse mutants developed structural changes in skeletal muscles, characterized by a frequent occurrence of ring fibers, internalized nuclei and disturbed mitochondrial distribution, as well as deficits in motor functions and moderate muscle weakness. These changes reflect symptoms of human myopathies. In the second manuscript, "Cyclase-associated protein 2 (CAP2) controls MRTF-A localization and SRF activity in mouse embryonic fibroblasts", we reported that loss of CAP2 in mouse embryonic fibroblasts lead to disturbed SRF activity. Specifically, we found that CAP2 controls subcellular distribution of the SRF trans-activator MRTF in an actin-dependent mechanism. CAP2 inactivation was associated with reduced nuclear MRTF levels and impaired SRF-mediated gene expression. This suggests that CAP2-dependent actin dynamics may also control SRF activity during skeletal muscle development and that dysregulation of SRF may cause or at least contribute to the myopathy in CAP2 mutant mice.