Marking the tempo for myogenesis: Pax7 and the regulation of muscle stem cell fate decisions

Abstract

Post-natal growth and regeneration of skeletal muscle is highly dependent on a population of resident myogenic precursors known as satellite cells. Transcription factors from the Pax gene family, Pax3 and Pax7, are critical for satellite cell biogenesis, survival and potentially self-renewal; however, the underlying molecular mechanisms remain unsolved. This is particularly true in the case of Pax7, which appears to regulate myogenesis at multiple levels. Accordingly, recent data have highlighted the importance of a functional relationship between Pax7 and the MyoD family of muscle regulatory transcription factors during normal muscle formation and disease. Here we will critically review key findings suggesting that Pax7 may play a dual role by promoting resident muscle progenitors to commit to the skeletal muscle lineage while preventing terminal differentiation, thus keeping muscle progenitors poised to differentiate upon environmental cues. In addition, potential regulatory mechanisms for the control of Pax7 activity will be proposed.

Fig 1

Satellite cells and skeletal muscle regeneration. In resting and uninjured muscles, satellite cells reside quiescent (green) sandwiched between the muscle fibre (multi-nucleated cell) plasma membrane and the basal lamina (not depicted). Upon external stimuli such as muscle injury (blue flash symbol), satellite cells become activated (yellow/green), re-enter the cell cycle and commit to the muscle lineage. After a few rounds of proliferation, myoblasts (yellow/ orange) undergo terminal differentiation (red cells) and fuse one to another to form new myotubes (red syncytia) or to pre-existing damaged fibres. During the process of myofibre repair, the pool of quiescent satellite cells is renewed.

Fig 2

Proposed model for Pax7 function as a Pan gene. Pax7 (and possibly Pax7/Pax3 during embryonic development) are required for acquisition of muscle commitment (yellow/orange cell) by inducing the expression of MyoD (and/or Myf-5). MyoD will eventually activate the expression of key targets such as myogenin (red cells), directing progression trough myogenesis and terminal differentiation (pink multi-nucleated cell). Pax7 may act downstream the induction of MyoD expression regulating MyoD activity, preventing myogenin induction and thus, muscle differentiation. This dual role of Pax7 may allow for the expression of key myogenic factors in an undifferentiated state, keeping a cell poised to rapidly differentiate on external stimuli.

Fig 3

Proposed model for the significance of Pax7:MRF protein ratios and satellite cell fate decisions. Modified from Olguin et al. (2007). Satellite cells (Pax7+/MyoD−/myogenin−) must commit to proliferate, differentiate or renew the progenitor population to maintain muscle function. Extrinsic signalling activates satellite cells and up-regulate MyoD (orange) with a concomitant decline in Pax7 expression (grey). Upon commitment to terminal differentiation, up-regulation of myogenin (red) directly or indirectly down-regulates Pax7. In a small subset, Pax7 down-regulation is prevented by unknown mechanisms resulting in MyoD down-regulation, blocking myogenin induction and eventually leading to the commitment to a quiescent, undifferentiated phenotype (yellow cell, black nucleus). In this model, the Pax7:MyoD expression ratio is regulated primarily by post-translational regulation of Pax7 and MyoD. Black arrowheads indicate putative control points (discussed in the text) where regulation of Pax7 activity/stability may participate in the control of satellite cell fate decisions.

Fig 4

Extracellular regulation of satellite cell fate. Extracellular signalling pathways that participate in the regulation of satellite cell fate and are associated with positive regulation of Pax7 expression/function are depicted in green. Signalling pathways exhibiting negative regulation of Pax7 expression/function are depicted in orange. Molecules that function in the same pathway (e.g. Syndecan-3 and Notch; Wnt and β-catenin) or leading to equivalent downstream effects in muscle progenitors (such as Syndecan-4 and p38), are depicted in common boxes. Signalling pathways that affect satellite cell fate but have no clearly defined effects on Pax7 expression/function are not depicted. Dotted lines indicate effects on satellite cell fate that are currently less defined or controversial. Extracellular signalling can direct the transition from one status to another (black arrows), or can stabilize a specific status (coloured cells). Green cells: uncommitted progenitor (i.e. recently activated and/or quiescent satellite cells); green/yellow cells: self-renewing satellite cells; yellow/orange cells: proliferating, MyoD+ muscle precursors (i.e. adult myoblasts); red cells: myogenin+, differentiating myocytes; pink multi-nucleated cell: myofibre.