SRF-MRTF signaling suppresses brown adipocyte development by modulating TGF-β/BMP pathway. (15th September 2020)

• Record Type: Journal Article
• Authors: Liu, Ruya; Xiong, Xuekai; Nam, Deokhwa; Yechoor, Vijay; Ma, Ke
• Is Part Of: Molecular and cellular endocrinology. Volume 515(2020)
• Publication Date: 2020-09-15
• Subjects: Serum response factor -- Myocardin-related transcription factors -- Actin cytoskeleton -- Brown adipogenesis; SRF serum response factor -- MRTF Myocardin-related transcription factor -- TGF-β transforming growth factor-β -- BMP bone morphogenic protein; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2020.110920
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: The SRF/MRTF and upstream signaling cascade play key roles in actin cytoskeleton organization and myocyte development. To date, how this signaling axis may function in brown adipocyte lineage commitment and maturation has not been delineated. Here we report that MRTF-SRF signaling exerts inhibitory actions on brown adipogenesis, and suppressing this negative regulation promotes brown adipocyte lineage development. During brown adipogenic differentiation, protein expressions of SRF, MRTFA/B and its transcription targets were down-regulated, and MRTFA/B shuttled from nucleus to cytoplasm. Silencing of SRF or MRTF-A/MRTF-B enhanced two distinct stages of brown adipocyte development, mesenchymal stem cell determination to brown adipocytes and terminal differentiation of brown adipogenic progenitors. We further demonstrate that the MRTF-SRF axis exerts transcriptional regulations of the TGF-β and BMP signaling pathway, critical developmental cues for brown adipocyte development. TGF-β signaling activity was significantly attenuated, whereas that of the BMP pathway augmented by inhibition of SRF or MRTF-A/MRTF-B, leading to enhanced brown adipocyte differentiation. Our study demonstrates the MRTF-SRF transcriptional cascade as a negative regulator of brown adipogenesis, through its transcriptional control of the TGF-β/BMP signaling pathways. Graphical abstract: Image 1 Highlights: SRF-MRTF pathway expression and activity are down-regulated during brown adipocyte maturation. Silencing of SRF or MRTF-A/MRTF-B promotes mesenchymal stem cell commitment to the brown adipocyte lineage. Inhibition of SRF or MRTF-A/MRTF-B enhances brown preadipocyte terminal differentiation. Suppressing SRF/MRTF attenuates TGF-β signaling while augmenting BMP pathway activity.