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Abstract

Stem cells display intrinsic interferon signaling, which protects them from viral infections. In the aging brain, the increased presence of interferons drives a decline in function in neural stem cells, yet the role of interferon in the young brain is poorly studied. Regardless of whether in the young or old brain, how interferon regulates neural stem cells and whether the intrinsic signaling contributes to the modulation of neurogenesis also remains unknown. Here, I apply single-cell transcriptomics to mice lacking type-I and -II interferon receptors, to assess the presence of interferon regulation in the young and old brains. I find that interferons act selectively on neural stem cells, and not neural progenitors, both in the young and the old brain. This selective role of interferons contributes to shaping the intrinsic interferon signaling in neural stem cells. To unveil the molecular underpinnings of the interferon response, I profile the cell cycle progression, transcriptome, translatome, and phospho-proteome of neural stem cells exposed to interferon β. Briefly, interferon β transiently activates mTORC1 while simultaneously arresting neural stem cells in G0, quiescence state. Importantly, the observed uncoupling of mTORC1 and cell cycle by interferon β represses the translation of the key stem cell activity factor Sox2. In addition, interferon β induces a late shutdown of protein synthesis in neural stem cells, mediated by the inhibition of mTORC1 and the upregulation of p-eIF2αS51. This biphasic regulation of mTORC1 activity and inhibition of cell cycle promotes the exit of the activation state of neural stem cells. Last, I identify IFIT1 as a key effector of the interferon-mediated modulation of neurogenesis in neural stem cells. Unpublished results from my group indicate a novel role of IFIT1 in binding eukaryotic mRNAs in neural stem cells, which suggests a potential role of IFIT1 in neurogenesis. My results show that the absence of IFIT1 impairs the dynamics of the neurogenic niches at all ages in the adult brain, as well as their social traits, learning capacity, and memory acquisition. Overall, I profile the molecular underpinnings of the interferon response in neural stem cells and unveil the regulatory role of interferons in regulating neural stem cells in the young homeostatic brain. This regulatory role of interferons on stemness at all ages reveals novel therapeutic implications of interferons not only in neurogenesis but also in cancer and viral infections in the brain as well as neurodegenerative disorders.