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Abstract
The development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons. We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A. Furthermore, iron-overload-induced developmental growth defects in C. elegans are ameliorated by vitamin E and A. We determine that all-trans retinoic acid activates the Retinoic Acid Receptor, which orchestrates the expression of anti-ferroptotic genes. In contrast, retinal and retinol show radical-trapping antioxidant activity. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids.
Neuronal development is tightly controlled by nutrients and antioxidants. Here, authors show that ferroptosis, a cell death modality driven by lipid peroxidation, is required to be suppressed by vitamin A or antioxidants to ensure proper neuronal development.
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1 Helmholtz Zentrum München, Research Unit Signaling and Translation, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525)
2 Helmholtz Zentrum München, Endogenous Retrovirus Group, Institute of Virology, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525)
3 Helmholtz Zentrum München, Computational Health Center, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); Ludwig-Maximilians University Munich, Department of Biology, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X)
4 Helmholtz Zentrum München, Institute of Functional Epigenetics, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525)
5 Memorial Sloan Kettering Cancer Center, Developmental Biology and Center for Stem Cell Biology, New York, USA (GRID:grid.51462.34) (ISNI:0000 0001 2171 9952)
6 Memorial Sloan Kettering Cancer Center, Developmental Biology and Center for Stem Cell Biology, New York, USA (GRID:grid.51462.34) (ISNI:0000 0001 2171 9952); Cincinnati Children’s Hospital Medical, UC Department of Pediatrics, Division of Developmental Biology, Cincinnati, USA (GRID:grid.239573.9) (ISNI:0000 0000 9025 8099)
7 Columbia University, Department of Biological Sciences, Department of Chemistry, Herbert Irving Comprehensive Cancer Center, Irving Institute for Cancer Dynamics, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729)
8 Helmholtz Zentrum München, Computational Health Center, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); University of Melbourne, Department of Biochemistry and Pharmacology, Parkville Victoria, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X)
9 Helmholtz Zentrum München, Endogenous Retrovirus Group, Institute of Virology, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); School of Medicine, Technical University of Munich, Institute of Virology, Munich, Germany (GRID:grid.6936.a) (ISNI:0000 0001 2322 2966)