title: The tumor suppressor p53 fine-tunes reactive oxygen species levels and neurogenesis via PI3 kinase signaling.
abstract: Mounting evidence points to a role for endogenous reactive oxygen species (ROS) in cell signaling, including in the control of cell proliferation, differentiation, and fate. However, the function of ROS and their molecular regulation in embryonic mouse neural progenitor cells (eNPCs) has not yet been clarified. Here, we describe that physiological ROS are required for appropriate timing of neurogenesis in the developing telencephalon in vivo and in cultured NPCs, and that the tumor suppressor p53 plays a key role in the regulation of ROS-dependent neurogenesis. p53 loss of function leads to elevated ROS and early neurogenesis, while restoration of p53 and antioxidant treatment partially reverse the phenotype associated with premature neurogenesis. Furthermore, we describe that the expression of a number of neurogenic and oxidative stress genes relies on p53 and that both p53 and ROS-dependent induction of neurogenesis depend on PI3 kinase/phospho-Akt signaling. Our results suggest that p53 fine-tunes endogenous ROS levels to ensure the appropriate timing of neurogenesis in eNPCs. This may also have implications for the generation of tumors of neurodevelopmental origin.
authors.affiliation: Laboratory for NeuroRegeneration and Repair, Department of Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany. kirsi.forsberg@medizin.uni-tuebingen.de
authors.forename: Kirsi
authors.initials: K
authors.lastname: Forsberg
authors.forename: Anja
authors.initials: A
authors.lastname: Wuttke
authors.forename: Giorgia
authors.initials: G
authors.lastname: Quadrato
authors.forename: Peter M
authors.initials: PM
authors.lastname: Chumakov
authors.forename: Andrea
authors.initials: A
authors.lastname: Wizenmann
authors.forename: Simone
authors.initials: S
authors.lastname: Di Giovanni
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis; D018384:Oxidative Stress / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013687:Telencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases