| Affiliation: | 1. Institute of Protein Biochemistry, National Research Council, Naples, Italy;2. Institute of Genetics and Biophysics, National Research Council, Naples, Italy;3. IRCCS INM, Neuromed, Pozzilli, Italy;4. International Mass Imaging Center, Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan;5. Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan;6. Istituto di Ricovero e Cura a Carattere Scientifico‐SDN, Naples, Italy;7. High Performance Computing and Networking Institute, National Research Council, Naples, Italy;8. Chemical Biology of Membranes and Therapeutic Delivery Unit, Institut Curie, INSERM U 1143, CNRS, UMR 3666, PSL Research University, Paris Cedex 05, France |
| 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. |
