A Molecular Switch Regulating Cell Fate Choice between Muscle Progenitor Cells and Brown Adipocytes

Abstract

During mouse embryo development, both muscle progenitor cells (MPCs) and brown adipocytes (BAs) are known to derive from the same Pax7/Myf5 progenitor cells. However, the underlying mechanisms for the cell fate control remain unclear. In Pax7-null MPCs from young mice, several BA-specific genes, including Prdm16 and Ucp1 and many other adipocyte-related genes, were upregulated with a concomitant reduction of Myod and Myf5, two muscle lineage-determining genes. This suggests a cell fate switch from MPC to BA. Consistently, freshly isolated Pax7-null but not wild-type MPCs formed lipid-droplet-containing UCP1 BA in culture. Mechanistically, MyoD and Myf5, both known transcription targets of Pax7 in MPC, potently repress Prdm16, a BA-specific lineage-determining gene, via the E2F4/p107/p130 transcription repressor complex. Importantly, inducible Pax7 ablation in developing mouse embryos promoted brown fat development. Thus, the MyoD/Myf5-E2F4/p107/p130 axis functions in both the Pax7/Myf5 embryonic progenitor cells and postnatal myoblasts to repress the alternative BA fate.

Cell Fate Determining Molecular Switches and Signaling Pathway in Pax7-expressing Somitic Mesoderm

“…(P-Q) Oil Red O staining of Pdgfra+/Thy1-cell culture. (P) Oil droplet staining in cells cultured in DMEM medium and (Q) in adipogenic medium (ADM) previously described (An et al, 2017). Scale bar: 50 μm in Q. P and Q share the same scale.…”

“…Previously it has been described that cell fate during mouse embryo development could be regulated with transcription factors. MyoD and Myf5 knockdown have been demonstrated to promote cell fate change in muscle progenitors to brown adipocytes (An et al, 2017), suggesting the possibility of cell fate reprogramming in Pax7 lineage at different developmental branch points. We have investigated other potential transcription factors, including Nfatc4 and Pitx3 at E12.5 between myogenic and fibroblast lineages, and Bcl11b and Meo2 at E14.5 between dermal and adipogenic lienages, that could be crucial in cell fate decision especially at different developmental branch point.…”

“…The sorted embryonic cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) with 10% fetal bovine serum (FBS). The adipogenic differentiation medium (ADM) was described previously (An et al, 2017). After reaching confluency, the cells were first cultured in ADM I for 2 days and then switched to ADM II for 2 days or more.…”

“…The development and differentiation of BAT depends heavily on networks of transcription factors including EBF2, PRDM16, PPARg and CEBPb (Wang and Seale, 2016), and intracellular signaling, such as BMP7 (Tseng et al, 2008); however, the early specification between BAT and muscle remains elusive. Our previous work demonstrated cell fate reprogramming between BAT and muscles (An et al, 2017), and we would like to further investigate in this direction. In contrast, much less is known about BAT and its progenitors.…”

“…The paradigm of Myf5 and Myod1 as the key fate determination factors, serving as upstream regulators of Myog and as markers of myogenic lineage commitment, is also well established (Buckingham and Relaix, 2007; Cossu et al, 1996). Linking these two observations, we recently demonstrated that Pax7 expression serves as a molecular switch between muscle precursors and brown adipocytes (An et al, 2017): Pax7 directly upregulates Myf5 and Myod1, which suppress brown fat fate choice by inhibiting Prdm16 through targeting E2f4 (An et al, 2017). This Pax7-Myf5/Myod1-E2f4-Prdm16 axis explains why Pax7 expression is maintained in muscle lineage, but not in brown adipose tissue (BAT) (Buckingham and Relaix, 2007).…”