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

ABSTRACT: 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.

SUBMITTER: Wang T

PROVIDER: S-EPMC8628544 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Wang Ting T Wang Zheng Z de Fabritus Lauriane L Tao Jinglian J Saied Essa M EM Lee Ho-Joon HJ Ramazanov Bulat R BR Jackson Benjamin B Burkhardt Daniel D Parker Mikhail M Gleinich Anne S AS Wang Zhirui Z Seo Dong Eun DE Zhou Ting T Xu Shihao S Alecu Irina I Azadi Parastoo P Arenz Christoph C Hornemann Thorsten T Krishnaswamy Smita S van de Pavert Serge A SA Kaech Susan M SM Ivanova Natalia B NB Santori Fabio R FR

Developmental cell 20211110 22

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 lymphati ...[more]

PMID: 34762852

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Project description:BackgroundCOUP transcription factors are required for the regulation of gene expression underlying development, differentiation, and homeostasis. They have an evolutionarily conserved function, being a known marker for neurogenesis from cnidarians to vertebrates. A homologue of this gene was shown previously to be a neuronal and nematocyte differentiation marker in Hydra. However, COUP-TFs had not previously been studied in a colonial cnidarian.Methodology/principal findingsWe cloned a COUP-TF homologue from the colonial marine cnidarian Hydractinia echinata. Expression of the gene was analysed during normal development, allorecognition events and ectopic Wnt activation, using in situ hybridisation and quantitative PCR. During normal Hydractinia development, the gene was first expressed in post-gastrula stages. It was undetectable in larvae, and its mRNA was present again in putative differentiating neurons and nematocytes in post-metamorphic stages. Global activation of canonical Wnt signalling in adult animals resulted in the upregulation of COUP-TF. We also monitored a strong COUP-TF upregulation in stolons undergoing allogeneic interactions. COUP-TF mRNA was most concentrated in the tissues that contacted allogeneic, non-self tissues, and decreased in a gradient away from the contact area. Interestingly, the gene was transiently upregulated during initial contact of self stolons, but dissipated rapidly following self recognition, while in non-self contacts high expression levels were maintained.Conclusions/significanceWe conclude that COUP-TF is likely involved in neuronal/nematocyte differentiation in a variety of contexts. This has now been shown to include allorecognition, where COUP-TF is thought to have been co-opted to mediate allorejection by recruiting stinging cells that are the effectors of cytotoxic rejection of allogeneic tissue. Our findings that Wnt activation upregulates COUP-TF expression suggests that Wnts' role in neuronal differentiation could be mediated through COUP-TF.

Dataset Information

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

Publications

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

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