Why the study?
Little is known about the molecular processes guiding sarcomere assembly in vivo, despite deficits in this process being a major cause of human disease.
Mob4 interacts with the chaperonin TRiC within the STRIPAK complex to coordinate the growth of myofibril and microtubule networks in vivo.
Zebrafish mob4 mutants reveal sarcomere defects; extends STRIPAK-TRiC roles in myofibril assembly but leaves open human disease relevance.
Myofibrils of the skeletal muscle are comprised of sarcomeres that generate force by contraction when myosin-rich thick filaments slide past actin-based thin filaments. Surprisingly little is known about the molecular processes that guide sarcomere assembly in vivo, despite deficits within this process being a major cause of human disease. To overcome this knowledge gap, we undertook a forward genetic screen coupled with reverse genetics to identify genes required for vertebrate sarcomere assembly. In this screen, we identified a zebrafish mutant with a nonsense mutation in mob4. In Drosophila, mob4 has been reported to play a role in spindle focusing as well as neurite branching and in planarians mob4 was implemented in body size regulation. In contrast, zebrafish mob4geh mutants are characterised by an impaired actin biogenesis resulting in sarcomere defects. Whereas loss of mob4 leads to a reduction in the amount of myofibril, transgenic expression of mob4 triggers an increase. Further genetic analysis revealed the interaction of Mob4 with the actin-folding chaperonin TRiC, suggesting that Mob4 impacts on TRiC to control actin biogenesis and thus myofibril growth. Additionally, mob4geh features a defective microtubule network, which is in-line with tubulin being the second main folding substrate of TRiC. We also detected similar characteristics for strn3-deficient mutants, which confirmed Mob4 as a core component of STRIPAK and surprisingly implicates a role of the STRIPAK complex in sarcomerogenesis.
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Berger et al. (2022) studied Myofibril and microtubule network growth. mob4 mutation vs. Wildtype siblings was evaluated on Muscle birefringence (p=<0.001).
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