BRAF activates PAX3 to control muscle precursor cell migration during forelimb muscle development
- Max-Planck-Institute for Heart and Lung Research, Germany
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.
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Author details
Funding
Deutsche Forschungsgemeinschaft (SFB TRR81 TP02)
- Thomas Braun
LOEWE Center for Cell and Gene Therapy
- Thomas Braun
German Center for Cardiovascular Research
- Thomas Braun
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures involving animals and their care were carried out in accordance with the guidelines for animal experiments at the Max-Planck-Institute for Heart and Lung Research, which conform to the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996) and the European Parliament Directive 2010/63/EU and the 22 September 2010 Council on the protection of animals. Animal experimentation was approved by the local Ethics committee for animal experiments at the Regierungspräsidium Darmstadt (Registration # B2/1015 „Herstellung transgener Mauslinien; Inaktivierung und Überexpression von Genen"). The animal house at the MPI-HLR is registered according to {section sign}11 German Animal Welfare Law.
Copyright
© 2016, Shin et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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BRAF activates PAX3 to control muscle precursor cell migration during forelimb muscle development
eLife 5:e18351.
https://doi.org/10.7554/eLife.18351
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