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FGF primes angioblast formation by inducing ETV2 and LMO2 via FGFR1/BRAF/MEK/ERK

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Abstract

It is critical to specify a signal that directly drives the transition that occurs between cell states. However, such inferences are often confounded by indirect intercellular communications or secondary transcriptomic changes due to primary transcription factors. Although FGF is known for its importance during mesoderm-to-endothelium differentiation, its specific role and signaling mechanisms are still unclear due to the confounding factors referenced above. Here, we attempted to minimize the secondary artifacts by manipulating FGF and its downstream mediators with a short incubation time before sampling and protein-synthesis blockage in a low-density angioblastic/endothelial differentiation system. In less than 8 h, FGF started the conversion of KDRlow/PDGFRAlow nascent mesoderm into KDRhigh/PDGFRAlow angioblasts, and the priming by FGF was necessary to endow endothelial formation 72 h later. Further, the angioblastic conversion was mediated by the FGFR1/BRAF/MEK/ERK pathway in mesodermal cells. Finally, two transcription factors, ETV2 and LMO2, were the early direct functional responders downstream of the FGF pathway, and ETV2 alone was enough to complement the absence of FGF. FGF’s selective role in mediating the first-step, angioblastic conversion from mesoderm-to-endothelium thus allows for refined control over acquiring and manipulating angioblasts. The noise-minimized differentiation/analysis platform presented here is well-suited for studies on the signaling switches of other mesodermal-lineage fates as well.

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Funding

The study was supported by the Ministry of Science and Technology, Taiwan (107-2314-B-006-025, 108-2320-B-006-028 and 109-2320-B-006-029).

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Author notes

  1. Peng-Chieh Chen and Ya-Wen Hsueh contributed equally.

Authors and Affiliations

  1. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35, Xiaodong Rd., Tainan, 70457, Taiwan

    Peng-Chieh Chen, Ya-Wen Hsueh, Kuen-Jer Tsai & Po-Min Chiang

  2. Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Peng-Chieh Chen, Ya-Wen Hsueh, Kuen-Jer Tsai & Po-Min Chiang

  3. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

    Yi-Hsuan Lee

  4. Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Hung-Wen Tsai

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  1. Peng-Chieh Chen
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Contributions

PC and PC designed research; PC, YH, YL, HT, KT and PC analyzed the data; PC, YH and PC performed research; PC and PC wrote the paper; HT, KT contributed new reagents or analytic tools.

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Correspondence to Po-Min Chiang.

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Chen, PC., Hsueh, YW., Lee, YH. et al. FGF primes angioblast formation by inducing ETV2 and LMO2 via FGFR1/BRAF/MEK/ERK. Cell. Mol. Life Sci. 78, 2199–2212 (2021). https://doi.org/10.1007/s00018-020-03630-8

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  • DOI: https://doi.org/10.1007/s00018-020-03630-8

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