The role of Hippo pathway members YAP1, TAZ, TEAD1, and TEAD4 in skeletal muscle fibers and at the neuromuscular junction

• Applicant: Professor Dr. Said Hashemolhosseini
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 345115526

Several signaling pathways are involved in developmental and homeostatic processes during myogenesis. During the last funding period, my lab investigated the role of the canonical Wnt signaling pathway and the Hippo pathway regulators YAP1, TAZ, TEAD1, and TEAD4, in skeletal muscle. We have demonstrated the activity of the canonical Wnt signaling pathway in subtypes of adult fast muscle fibers that differ from the same fibers without activated canonical Wnt signaling by a smaller fiber diameter and we discovered an active YAP1/TAZ signaling pathway in the same fibers. In the course of our work, we were able to show for the first time that YAP1/TAZ/TEAD-mediated and canonical Wnt signaling activities coexist and work in concert in muscle fibers. During the last funding period, we successfully completed several projects. First, we established conditional mouse models to study the role of both pathways. Second, we published the involvement of the Wnt repressors TLE3 and TLE4 in the successful clustering of postsynaptic acetylcholine receptors. Third, we published data on the phenotype following knockout of Lrp5 or Lrp6 co-receptors of the canonical Wnt pathway in skeletal muscle. Fourth, we observed embryonic lethality in conditional Lrp5/Lrp6 double knockout mice and initial evidence points to ectopic Cre recombinase in cardiomyocytes as the cause. Fifth, we published that YAP1 and TAZ are directly involved in the regulation of postsynaptic gene expression via TEAD1 and TEAD4, and that simultaneous knockout of Yap1 and TAZ results in failure to form the postsynaptic apparatus and neonatal lethality. Sixth, our preliminary data analyzing the transcriptome of Yap1/Taz-deficient skeletal muscle fibers suggest an involvement in the transcription of sarcomere genes. With the projects presented in this proposal, we aim to elucidate the role of the YAP1/TAZ-TEAD signaling pathway in early myogenesis, skeletal muscle development, adult skeletal muscle fibers, neuromuscular junction (NMJ) and regeneration in the next funding period. We also would like to extend our studies to the TEAD1 and TEAD4 transcription factors downstream of YAP1/TAZ using appropriate conditional mouse models. We have received written commitments from several of the world's leading laboratories to support our approach with mouse models and expertise. Our research will further elucidate the molecular role of signaling pathways and thus contribute to future molecularly targeted therapeutic interventions.

• DFG Programme: Research Grants