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...

Full description

Saved in:
Bibliographic Details
Published in:The EMBO journal Vol. 37; no. 7
Main Authors: 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
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 03.04.2018
Springer Nature B.V
EMBO Press
John Wiley and Sons Inc
Subjects:
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
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography: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