Abstract
Skeletal muscle regeneration and long term maintenance is directly link to the balance between self-renewal and differentiation of resident adult stem cells known as satellite cells. In turn, satellite cell fate is influenced by a functional interaction between the transcription factor Pax7 and members of the MyoD family of muscle regulatory factors. Thus, changes in the Pax7-to-MyoD protein ratio may act as a molecular rheostat fine-tuning acquisition of lineage identity while preventing precocious terminal differentiation. Pax7 is expressed in quiescent and proliferating satellite cells, while its levels decrease sharply in differentiating progenitors Pax7 is maintained in cells (re)acquiring quiescence. While the mechanisms regulating Pax7 levels based on differentiation status are not well understood, we have recently described that Pax7 levels are directly regulated by the ubiquitin-ligase Nedd4, thus promoting proteasome-dependent Pax7 degradation in differentiating satellite cells. Here we show that Pax7 levels are maintained in proliferating muscle progenitors by a mechanism involving casein kinase 2-dependent Pax7 phosphorylation at S201. Point mutations preventing S201 phosphorylation or casein kinase 2 inhibition result in decreased Pax7 protein in proliferating muscle progenitors. Accordingly, this correlates directly with increased Pax7 ubiquitination. Finally, Pax7 down regulation induced by casein kinase 2 inhibition results in precocious myogenic induction, indicating early commitment to terminal differentiation. These observations highlight the critical role of post translational regulation of Pax7 as a molecular switch controlling muscle progenitor fate.
Highlights
Satellite cells (SCs) are tissue specific stem cells present in the adult skeletal muscle and largely responsible for its regenerative capacity [1,2,3]
Further inspection of the identified phosphopeptides revealed that Pax7 S201 and S205 were located in two consecutive casein kinase 2 (CK2) consensus sites (Fig 1B)
Since no products were detected in the absence of CK2 or Pax7, these results indicate that Pax7 is phosphorylated by CK2 at S201
Summary
Satellite cells (SCs) are tissue specific stem cells present in the adult skeletal muscle and largely responsible for its regenerative capacity [1,2,3]. Whereas it is well stablished that muscle differentiation is under the transcriptional control of the MyoD family, the molecular regulation of SC maintenance and renewal has recently begun to unveil. In this regard, the transcription factor Pax is required for SC specification [9,10,11] and function [12,13]. Nedd knockdown prevents terminal muscle differentiation [21] It is unclear how Nedd localization is controlled nor the mechanisms coordinating Pax retention in self-renewing progenitors and down regulation in differentiating cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
