During mouse embryo development, Pax7⁺/Myf5⁺ progenitor cells give rise to both muscle progenitor cells (MPC) and brown adipocytes (BA). The underlying mechanisms for the cell fate determination between muscle and brown fat remain unclear. In MPC depleted for Pax7, two myogenic regulatory factors Myod and Myf5 were reduced while several BA-specific genes including Prdm16 and Ucp1 and many other adipocyte-related genes were unexpectedly upregulated. This suggests loss of Pax7 caused a cell fate switch from MPC to BA. Consistently, freshly-isolated Pax7-null but not wild-type MPC formed lipid droplet-containing, UCP1⁺ brown adipocytes in culture. Mechanistically, MyoD and Myf5 act downstream of Pax7 to repress Prdm16, a BA-specific lineage-determining gene. Thus, MyoD and Myf5 ac...[ Read more ]

During mouse embryo development, Pax7⁺/Myf5⁺ progenitor cells give rise to both muscle progenitor cells (MPC) and brown adipocytes (BA). The underlying mechanisms for the cell fate determination between muscle and brown fat remain unclear. In MPC depleted for Pax7, two myogenic regulatory factors Myod and Myf5 were reduced while several BA-specific genes including Prdm16 and Ucp1 and many other adipocyte-related genes were unexpectedly upregulated. This suggests loss of Pax7 caused a cell fate switch from MPC to BA. Consistently, freshly-isolated Pax7-null but not wild-type MPC formed lipid droplet-containing, UCP1⁺ brown adipocytes in culture. Mechanistically, MyoD and Myf5 act downstream of Pax7 to repress Prdm16, a BA-specific lineage-determining gene. Thus, MyoD and Myf5 activate a transcription repressor E2f4 which directly suppresses Prdm16 with p107 or p130. miR-133a which is another target of MyoD and Myf5 represses Prdm16 post-transcriptionally in parallel with E2F4. Importantly, inducible Pax7 ablation in developing mouse embryos promoted brown fat development by switching the fate of dermomyotomal progenitors. Thus, the MyoD/Myf5-E2F4/p107/p130 axis functions in both the Pax7⁺/Myf5⁺ embryonic progenitor cells and postnatal myoblasts to repress the alternative brown adipogenic fate. In addition, the repression mechanism for Prdm16 by E2F4 is also conserved in white pre-adipocytes.