Glycosphingolipid metabolic reprogramming drives neural differentiation

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...

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Vydáno v:	The EMBO journal Ročník 37; číslo 7
Hlavní autoři:	Russo, Domenico, Della Ragione, Floriana, Rizzo, Riccardo, Sugiyama, Eiji, Scalabrì, Francesco, Hori, Kei, Capasso, Serena, Sticco, Lucia, Fioriniello, Salvatore, De Gregorio, Roberto, Granata, Ilaria, Guarracino, Mario R, Maglione, Vittorio, Johannes, Ludger, Bellenchi, Gian Carlo, Hoshino, Mikio, Setou, Mitsutoshi, D'Esposito, Maurizio, Luini, Alberto, D'Angelo, Giovanni
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 03.04.2018 Springer Nature B.V EMBO Press John Wiley and Sons Inc
Témata:	Acetylation AUTS2 bistability Cell differentiation Cell Differentiation - drug effects Cell Differentiation - genetics Cell Differentiation - physiology Cellular Reprogramming - drug effects Cellular Reprogramming - physiology Circuits Constraining Cytoskeletal Proteins Differentiation (biology) EMBO21 EMBO27 Enzymes epigenetics Epigenomics Gangliosides Gangliosides - metabolism Gene Expression Gene Silencing Glycosphingolipids Glycosphingolipids - metabolism Glycosphingolipids - pharmacology HeLa Cells Histones - metabolism Humans Lactosylceramide a-2,3-sialyltransferase Life Sciences Metabolism Molecular modelling neural differentiation Neural stem cells Neurodevelopmental Disorders Neurogenesis - drug effects Neurogenesis - genetics Neurogenesis - physiology Neurons - metabolism Promoter Regions, Genetic - drug effects Proteins - genetics Proteins - metabolism Sialyltransferases - genetics Sialyltransferases - metabolism Stem cells Transcription Factors bistability AUTS2 neural differentiation epigenetics glycosphingolipids
ISSN:	0261-4189, 1460-2075, 1460-2075
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Shrnutí:	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. Synopsis Schematic representation of glycosphingolipid reprogramming circuit in neural differentiation. Globo‐series glycosphingolipids inhibit the production of ganglio‐series glycosphingolipids. AUTS2 expression is repressed by globo‐series glycosphingolipids. AUTS2 activates the promoter of the first and rate limiting enzyme involved in ganglio‐series glycosphingolipids production i.e., GM3 synthase by inducing histone acetylation. The globo‐AUTS2 axis regulates the expression of neuronal genes during neural differentiation. The decrease of globo‐series glycosphingolipids is required for AUTS2 induction and for stem cell differentiation to neural cells. Graphical Abstract The switch from globo‐ to ganglio‐series glycophospholipids during neurodevelopment involves a self‐contained regulatory circuit controlling expression of both neuronal and ganglioside‐producing genes.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 See also: https://doi.org/10.15252/embj.201899221 (April 2018)
ISSN:	0261-4189 1460-2075 1460-2075
DOI:	10.15252/embj.201797674