Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation Rodríguez Vargas, José Manuel Martin-Hernandez, Kathline Wang, Wei Kunath, Nicolas Suganthan, Rajikala Amé, Jean-Christophe Oliver, F Javier Ye, Jing Bjørås, Magnar Dantzer, Francoise PARP3 Neurogenesis Astrocytes Differentiation This work was funded by USIAS-2017-029 fellowship (to F.D) and Ramon Areces Foundation (to J-M.R). The lab of F.D. is supported by Strasbourg University, Centre National de la recherche Scientifique and the LABEX ANR-10- LABX-0034_Medalis. Sequencing was performed by the GenomEast platform, a member of the “France Génomique” consortium (ANR-10-INSB-0009). The lab of M.B is supported by Health Authorities of Norway, Cancer Society of Norway, Research Council of Norway. Parp3 is a member of the Poly(ADP-ribose) polymerase (Parp) family that has been characterized for its functions in strand break repair, chromosomal rearrangements, mitotic segregation and tumor aggressiveness. Yet its physiological implications remain unknown. Here we report a central function of Parp3 in the regulation of redox homeostasis in continuous neurogenesis in mice. We show that the absence of Parp3 provokes Nox4-induced oxidative stress and defective mTorc2 activation leading to inefficient differentiation of post-natal neural stem/progenitor cells to astrocytes. The accumulation of ROS contributes to the decreased activity of mTorc2 as a result of an oxidationinduced and Fbxw7-mediated ubiquitination and degradation of Rictor. In vivo, mTorc2 signaling is compromised in the striatum of naïve post-natal Parp3-deficient mice and 6 h after acute hypoxia-ischemia. These findings reveal a physiological function of Parp3 in the tight regulation of striatal oxidative stress and mTorc2 during astrocytic differentiation and in the acute phase of hypoxia-ischemia. 2026-02-12T08:22:59Z 2026-02-12T08:22:59Z 2020-11-06 journal article Rodriguez-Vargas, JM., Martin-Hernandez, K., Wang, W. et al. (2020). Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation. Cell Death and Disease 11, 954. https://doi.org/10.1038/s41419-020-03167-5 2041-4889 https://hdl.handle.net/10481/110907 10.1038/s41419-020-03167-5 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Springer Nature