NEDD4 Regulates PAX7 Levels Promoting Activation of the Differentiation Program in Skeletal Muscle Precursors

• Published in: Stem cells (Dayton, Ohio) Vol. 33; no. 10; pp. 3138 - 3151
• Main Authors: Bustos, Francisco, de la Vega, Eduardo, Cabezas, Felipe, Thompson, James, Cornelison, D.D.W., Olwin, Bradley B., Yates, John R., Olguín, Hugo C.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.10.2015
• Subjects: Animals; Cell Differentiation - genetics; Cell Proliferation - genetics; Endosomal Sorting Complexes Required for Transport - biosynthesis; Endosomal Sorting Complexes Required for Transport - genetics; Gene Expression Regulation, Developmental; Humans; Mice; Muscle Development; Muscle, Skeletal - growth & development; Muscle, Skeletal - metabolism; Musculoskeletal system; MyoD Protein - biosynthesis; Nedd4; Nedd4 Ubiquitin Protein Ligases; Pax7; PAX7 Transcription Factor - biosynthesis; PAX7 Transcription Factor - genetics; Proteasome; Proteasome Endopeptidase Complex - genetics; Satellite cells; Satellite Cells, Skeletal Muscle - cytology; Satellite Cells, Skeletal Muscle - metabolism; Skeletal muscle; Ubiquitin; Ubiquitin-Protein Ligases - biosynthesis; Ubiquitin-Protein Ligases - genetics; Ubiquitination; Ubiquitin; Satellite cells; Pax7; Skeletal muscle; Nedd4; Proteasome
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2125

The transcription factor Pax7 regulates skeletal muscle stem cell (satellite cells) specification and maintenance through various mechanisms, including repressing the activity of the muscle regulatory factor MyoD. Hence, Pax7‐to‐MyoD protein ratios can determine maintenance of the committed‐undifferentiated state or activation of the differentiation program. Pax7 expression decreases sharply in differentiating myoblasts but is maintained in cells (re)acquiring quiescence, yet the mechanisms regulating Pax7 levels based on differentiation status are not well understood. Here we show that Pax7 levels are directly regulated by the ubiquitin‐ligase Nedd4. Our results indicate that Nedd4 is expressed in quiescent and activated satellite cells, that Nedd4 and Pax7 physically interact during early muscle differentiation—correlating with Pax7 ubiquitination and decline—and that Nedd4 loss of function prevented this effect. Furthermore, even transient nuclear accumulation of Nedd4 induced a drop in Pax7 levels and precocious muscle differentiation. Consequently, we propose that Nedd4 functions as a novel Pax7 regulator, which activity is temporally and spatially controlled to modulate the Pax7 protein levels and therefore satellite cell fate. Stem Cells 2015;33:3138—3151 Ubiquitin‐ligase Nedd4 down regulates Pax7 levels in a cell context‐dependent manner, allowing progression through the myogenic program in adult muscle progenitors.