Sirt7-p21 Signaling Pathway Mediates Glucocorticoid-Induced Inhibition of Mouse Neural Stem Cell Proliferation
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ORIGINAL ARTICLE
Sirt7-p21 Signaling Pathway Mediates Glucocorticoid-Induced Inhibition of Mouse Neural Stem Cell Proliferation Mohammed A. H. Alnoud 1 & Wen Chen 1 & Nana Liu 1 & Wei Zhu 1 & Jing Qiao 1 & Shujuan Chang 1 & Yukang Wu 1 & Shanshan Wang 1 & Yiwei Yang 1 & Qiaoyi Sun 1 & Jiuhong Kang 1 Received: 4 May 2020 / Revised: 30 September 2020 / Accepted: 1 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Prenatal glucocorticoid (GC) overexposure impacts fetal hippocampal neural stem cells (NSCs) and increases the risk for relative cognitive and mood disorders in offspring. However, the precise underlying mechanisms remain elusive. Here, we treated mouse hippocampal NSCs with dexamethasone (DEX) in vitro and found that DEX inhibited cell proliferation and Sirt7 expression. In addition, prenatal mouse overexposure to DEX induced the suppression of Sirt7 in the hippocampus of offspring. Sirt7 knockdown significantly decreased the percentage of proliferating cells but did not further reduce the NSC proliferation rate in the presence of DEX, whereas Sirt7 overexpression rescued DEX-induced inhibition of hippocampal NSC proliferation. Moreover, DEX inhibited Sirt7 expression through the glucocorticoid receptor (GR), and p21 was found to mediate the functional effect of DEX-induced Sirt7 suppression. In conclusion, our data demonstrate for the first time the effect of DEX on the Sirt7-p21 pathway in hippocampal NSCs, identifying a new potential therapeutic target for prenatal GC overexposure–related neurodevelopmental disorders in offspring. Keywords Neural stem cells . Sirt7 . GR . p21 . Dexamethasone
Abbreviations NSCs Neural stem cells DEX Dexamethasone DG Dentate gyrus GR Glucocorticoid receptor GC Glucocorticoid P3W Postnatal 3 week GREs GC-responsive elements CDK Cyclin-dependent kinase MR Mineralocorticoid receptor
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12640-020-00294-x) contains supplementary material, which is available to authorized users. * Jiuhong Kang [email protected] 1
Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China
Introduction During late gestation in most mammalian species, there is a physiological surge in maternal glucocorticoids (GCs) that is critical for normal fetal organ development (Cole 2006; Moisiadis and Matthews 2014). Usually, synthetic GCs are administered to pregnant women at risk of preterm birth to promote the maturation of fetal lungs (Neilson 2007). Maternal GC exposure of the fetus is tightly controlled by placental 11βhydroxysteroid dehydrogenase (11β-HSD), which inactivates glucocorticoids and prevents prematuration of fetal organs. However, pathological conditions that impair placental functions or exogenous GC levels abo
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