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BRAF activates PAX3 to control muscle precursor cell migration during forelimb muscle development

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Shin,  Jaeyoung
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Watanabe,  Shuichi
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Hoelper,  Soraya
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Krüger,  Marcus
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Kostin,  Sawa
Electron Microscopy, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Poeling,  Jochen
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Kubin,  Thomas
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Braun,  Thomas
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Shin, J., Watanabe, S., Hoelper, S., Krüger, M., Kostin, S., Poeling, J., et al. (2016). BRAF activates PAX3 to control muscle precursor cell migration during forelimb muscle development. ELIFE, 5: e18351. doi:10.7554/elife.18351.


Cite as: http://hdl.handle.net/21.11116/0000-0001-BD77-5
Abstract
Migration of skeletal muscle precursor cells is a key step during limb muscle development and depends on the activity of PAX3 and MET. Here, we demonstrate that BRAF serves a crucial function in formation of limb skeletal muscles during mouse embryogenesis downstream of MET and acts as a potent inducer of myoblast cell migration. We found that a fraction of BRAF accumulates in the nucleus after activation and endosomal transport to a perinuclear position. Mass spectrometry based screening for potential interaction partners revealed that BRAF interacts and phosphorylates PAX3. Mutation of BRAF dependent phosphorylation sites in PAX3 impaired the ability of PAX3 to promote migration of C2C12 myoblasts indicating that BRAF directly activates PAX3. Since PAX3 stimulates transcription of the Met gene we propose that MET signaling via BRAF fuels a positive feedback loop, which maintains high levels of PAX3 and MET activity required for limb muscle precursor cell migration.