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

• Published in: Developmental cell 2017-05, Vol.41 (4), p.382-391.e5
• Main Authors: An, Yitai, Wang, Gang, Diao, Yarui, Long, Yanyang, Fu, Xinrong, Weng, Mingxi, Zhou, Liang, Sun, Kun, Cheung, Tom H., Ip, Nancy Y., Sun, Hao, Wang, Huating, Wu, Zhenguo
• Format: Article
• Language: English
• Subjects: Adipocytes, Brown - cytology; Adipocytes, Brown - metabolism; Adipose Tissue, Brown - embryology; Adipose Tissue, Brown - metabolism; Animals; brown adipocytes; cell fate control; Cell Line; Cell Lineage - genetics; Cells, Cultured; DNA-Binding Proteins - metabolism; E2F4 Transcription Factor - metabolism; E2F4/p107/p130; Embryo, Mammalian - metabolism; Gene Deletion; Gene Knockdown Techniques; Mice; muscle progenitor cells; Muscles - cytology; Myf5; MyoD; MyoD Protein - metabolism; Myogenic Regulatory Factor 5 - metabolism; Pax7; PAX7 Transcription Factor - metabolism; Prdm16; Repressor Proteins - metabolism; Stem Cells - cytology; Stem Cells - metabolism; Transcription Factors - metabolism; Transcription, Genetic; Ucp1; Up-Regulation - genetics
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2017.04.012

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. [Display omitted] •Deletion of Pax7 in muscle progenitor cells (MPCs) promotes brown fat development•Knockdown of MyoD or Myf5 in MPCs promotes a cell fate change to brown adipocytes•MyoD/Myf5 transcriptionally repress Prdm16 in MPCs via E2F4/pocket proteins•E2F4/pocket proteins directly bind and repress Prdm16 An, Wang, Diao et al. show that the MyoD/Myf5-E2F4/p107/p130 axis functions as a molecular switch in the Pax7+ embryonic progenitor cells or postnatal myoblasts to regulate the choice between myoblast and brown adipocyte cell fate. Turning off this switch transcriptionally upregulates Prdm16 and promotes the formation of brown adipocytes.