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.

SRF/MRTF 和上游信号级联在肌动蛋白细胞骨架组织和肌细胞发育中起关键作用。迄今为止，尚未描述该信号轴如何在棕色脂肪细胞谱系定型和成熟中发挥作用。在这里，我们报告了 MRTF-SRF 信号对棕色脂肪生成产生抑制作用，并且抑制这种负调节促进了棕色脂肪细胞谱系的发育。在棕色脂肪分化过程中，SRF、MRTFA/B 及其转录靶点的蛋白表达下调，MRTFA/B 从细胞核穿梭于细胞质。SRF 或 MRTF-A/MRTF-B 的沉默增强了棕色脂肪细胞发育的两个不同阶段，间充质干细胞对棕色脂肪细胞的测定和棕色脂肪细胞的终末分化。我们进一步证明 MRTF-SRF 轴发挥 TGF-β 和 BMP 信号通路的转录调控，这是棕色脂肪细胞发育的关键发育线索。TGF-β 信号传导活性显着减弱，而 BMP 通路的活性通过抑制 SRF 或 MRTF-A/MRTF-B 增强，导致棕色脂肪细胞分化增强。我们的研究表明 MRTF-SRF 转录级联是棕色脂肪生成的负调节因子，通过其对 TGF-β/BMP 信号通路的转录控制。导致增强的棕色脂肪细胞分化。我们的研究表明 MRTF-SRF 转录级联是棕色脂肪生成的负调节因子，通过其对 TGF-β/BMP 信号通路的转录控制。导致增强的棕色脂肪细胞分化。我们的研究表明 MRTF-SRF 转录级联是棕色脂肪生成的负调节因子，通过其对 TGF-β/BMP 信号通路的转录控制。