Glycosphingolipid metabolic reprogramming drives neural differentiation

Domenico Russo, Floriana Della Ragione, Riccardo Rizzo, Eiji Sugiyama, Francesco Scalabrì, Kei Hori, Serena Capasso, Lucia Sticco, Salvatore Fioriniello, Roberto De Gregorio, Ilaria Granata, Mario R. Guarracino, Vittorio Maglione, Ludger Johannes, Gian Carlo Bellenchi, Mikio Hoshino, Mitsutoshi Setou, Maurizio D'Esposito, Alberto Luini, Giovanni D'Angelo

Research output: Contribution to journalArticle

Abstract

Neural development is accomplished by differentiation events leading to metabolic reprogramming. Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo- to ganglio-series glycosphingolipid production. Failure to execute this glycosphingolipid switch leads to neurodevelopmental disorders in humans, indicating that glycosphingolipids are key players in this process. Nevertheless, both the molecular mechanisms that control the glycosphingolipid switch and its function in neurodevelopment are poorly understood. Here, we describe a self-contained circuit that controls glycosphingolipid reprogramming and neural differentiation. We find that globo-series glycosphingolipids repress the epigenetic regulator of neuronal gene expression AUTS2. AUTS2 in turn binds and activates the promoter of the first and rate-limiting ganglioside-producing enzyme GM3 synthase, thus fostering the synthesis of gangliosides. By this mechanism, the globo-AUTS2 axis controls glycosphingolipid reprogramming and neural gene expression during neural differentiation, which involves this circuit in neurodevelopment and its defects in neuropathology.

Original languageEnglish
JournalEMBO Journal
DOIs
Publication statusAccepted/In press - Jan 1 2017

Keywords

  • AUTS2
  • Bistability
  • Epigenetics
  • Glycosphingolipids
  • Neural differentiation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Russo, D., Della Ragione, F., Rizzo, R., Sugiyama, E., Scalabrì, F., Hori, K., Capasso, S., Sticco, L., Fioriniello, S., De Gregorio, R., Granata, I., Guarracino, M. R., Maglione, V., Johannes, L., Bellenchi, G. C., Hoshino, M., Setou, M., D'Esposito, M., Luini, A., & D'Angelo, G. (Accepted/In press). Glycosphingolipid metabolic reprogramming drives neural differentiation. EMBO Journal. https://doi.org/10.15252/embj.201797674