1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development

Dev Cell. 2021 Nov 22;56(22):3128-3145.e15. doi: 10.1016/j.devcel.2021.10.018. Epub 2021 Nov 10.


Identification of physiological modulators of nuclear hormone receptor (NHR) activity is paramount for understanding the link between metabolism and transcriptional networks that orchestrate development and cellular physiology. Using libraries of metabolic enzymes alongside their substrates and products, we identify 1-deoxysphingosines as modulators of the activity of NR2F1 and 2 (COUP-TFs), which are orphan NHRs that are critical for development of the nervous system, heart, veins, and lymphatic vessels. We show that these non-canonical alanine-based sphingolipids bind to the NR2F1/2 ligand-binding domains (LBDs) and modulate their transcriptional activity in cell-based assays at physiological concentrations. Furthermore, inhibition of sphingolipid biosynthesis phenocopies NR2F1/2 deficiency in endothelium and cardiomyocytes, and increases in 1-deoxysphingosine levels activate NR2F1/2-dependent differentiation programs. Our findings suggest that 1-deoxysphingosines are physiological regulators of NR2F1/2-mediated transcription.

Keywords: 1-deoxysphingosine; COUP-TF; NR2F1; NR2F2; NR2F6; SPTLC2; cardiomyocyte; lymphatic; metabolism; sphingolipid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Cell Differentiation / physiology
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / physiology
  • Humans
  • Lymphatic Vessels / drug effects
  • Mice
  • Organogenesis / drug effects*
  • Organogenesis / physiology
  • Repressor Proteins / physiology
  • Sphingolipids / pharmacology*


  • 1-deoxysphingolipid
  • Repressor Proteins
  • Sphingolipids