Skip to main content

Advertisement

SpringerLink
Log in

Sirt7-p21 Signaling Pathway Mediates Glucocorticoid-Induced Inhibition of Mouse Neural Stem Cell Proliferation

  • Original Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

A Correction to this article was published on 20 April 2021

This article has been updated

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Change history

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

References

  • Anacker C, Hen R (2017) Adult hippocampal neurogenesis and cognitive flexibility—linking memory and mood. Nat Rev Neurosci 18:335–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bertoli C, Skotheim JM, De Bruin RA (2013) Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol 14:518–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bose R, Moors M, Tofighi R, Cascante A, Hermanson O, Ceccatelli S (2010) Glucocorticoids induce long-lasting effects in neural stem cells resulting in senescence-related alterations. Cell Death Dis 1:e92–e92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cha HH, Cram EJ, Wang EC, Huang AJ, Kasler HG, Firestone GL (1998) Glucocorticoids stimulate p21 gene expression by targeting multiple transcriptional elements within a steroid responsive region of the p21 waf1/cip1 promoter in rat hepatoma cells. J Biol Chem 273:1998–2007

    Article  CAS  PubMed  Google Scholar 

  • Choy KHC, de Visser Y, Nichols NR, van den Buuse M (2008) Combined neonatal stress and young-adult glucocorticoid stimulation in rats reduce BDNF expression in hippocampus: effects on learning and memory. Hippocampus 18:655–667

    Article  CAS  PubMed  Google Scholar 

  • Cole TJ (2006) Glucocorticoid action and the development of selective glucocorticoid receptor ligands. Biotechnol Annu Rev 12:269–300

    Article  CAS  PubMed  Google Scholar 

  • Cram EJ, Ramos RA, Wang EC, Cha HH, Nishio Y, Firestone GL (1998) Role of the CCAAT/enhancer binding protein-α transcription factor in the glucocorticoid stimulation of p21 waf1/cip1 gene promoter activity in growth-arrested rat hepatoma cells. J Biol Chem 273:2008–2014

    Article  CAS  PubMed  Google Scholar 

  • de los Angeles GAM, del Carmen ROM, Wendy PM, Socorro R-M (2016) Tactile stimulation effects on hippocampal neurogenesis and spatial learning and memory in prenatally stressed rats. Brain Res Bull 124:1–11

    Article  Google Scholar 

  • Diaz-Perdigon T, Belloch FB, Ricobaraza A, Elboray EE, Suzuki T, Tordera RM, Puerta E (2020) Early sirtuin 2 inhibition prevents age-related cognitive decline in a senescence-accelerated mouse model. Neuropsychopharmacology 45:347–357

    Article  CAS  PubMed  Google Scholar 

  • Eichenbaum H, Cohen NJ (2014) Can we reconcile the declarative memory and spatial navigation views on hippocampal function? Neuron 83:764–770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eto I (2010) Upstream molecular signaling pathways of p27 (Kip1) expression: effects of 4-hydroxytamoxifen, dexamethasone, and retinoic acids. Cancer Cell Int 10:3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fusco S, Leone L, Barbati SA, Samengo D, Piacentini R, Maulucci G, Toietta G, Spinelli M, McBurney M, Pani G, Grassi C (2016) A CREB-Sirt1-Hes1 circuitry mediates neural stem cell response to glucose availability. Cell Rep 14:1195–1205

    Article  CAS  PubMed  Google Scholar 

  • G V, M L (2020) Genetics in endocrinology: glucocorticoid resistance syndrome. Eur J Endocrinol 182:R15–R27

    Article  Google Scholar 

  • Gao J, Wang W-Y, Mao Y-W, Gräff J, Guan J-S, Pan L, Mak G, Kim D, Su SC, Tsai LH (2010) A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466:1105–1109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han D, Gao J, Gu X, Hengstler JG, Zhang L, Shahid M, Ali T, Han B (2018) P21 Waf1/Cip1 depletion promotes dexamethasone-induced apoptosis in osteoblastic MC3T3-E1 cells by inhibiting the Nrf2/HO-1 pathway. Arch Toxicol 92:679–692

    Article  CAS  PubMed  Google Scholar 

  • Hauser J, Feldon J, Pryce CR (2009) Direct and dam-mediated effects of prenatal dexamethasone on emotionality, cognition and HPA axis in adult Wistar rats. Horm Behav 56:364–375

    Article  CAS  PubMed  Google Scholar 

  • Hauser J, Knapman A, Zürcher NR, Pilloud S, Maier C et al (2008) Effects of prenatal dexamethasone treatment on physical growth, pituitary-adrenal hormones, and performance of motor, motivational, and cognitive tasks in juvenile and adolescent common marmoset monkeys. Endocrinology 149:6343–6355

    Article  CAS  PubMed  Google Scholar 

  • Holmes MC, Abrahamsen CT, French KL, Paterson JM, Mullins JJ, Seckl JR (2006) The mother or the fetus? 11β-Hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. J Neurosci 26:3840–3844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Islam MS, Wei F-Y, Ohta K, Shigematsu N, Fukuda T, Tomizawa K, Yoshizawa T, Yamagata K (2018) Sirtuin 7 is involved in the consolidation of fear memory in mice. Biochem Biophys Res Commun 495:261–266

    Article  CAS  PubMed  Google Scholar 

  • Kawata M (1995) Roles of steroid hormones and their receptors in structural organization in the nervous system. Neurosci Res 24:1–46

    Article  CAS  PubMed  Google Scholar 

  • Kim J-H, Kim D, Cho SJ, Jung K-Y, Kim J-H, Lee JM, Jung HJ, Kim KR (2019) Identification of a novel SIRT7 inhibitor as anticancer drug candidate. Biochem Biophys Res Commun 508:451–457

    Article  CAS  PubMed  Google Scholar 

  • Kim JB, Ju JY, Kim JH, Kim T-Y, Yang B-H, Lee Y-S, Son H (2004) Dexamethasone inhibits proliferation of adult hippocampal neurogenesis in vivo and in vitro. Brain Res 1027:1–10

    Article  CAS  PubMed  Google Scholar 

  • Kino T (2015) Stress, glucocorticoid hormones, and hippocampal neural progenitor cells: implications to mood disorders. Front Physiol 6:230

    Article  PubMed  PubMed Central  Google Scholar 

  • Lautarescu A, Pecheva D, Nosarti C, Nihouarn J, Zhang H, Victor S, Craig M, Edwards AD, Counsell SJ (2020) Maternal prenatal stress is associated with altered uncinate fasciculus microstructure in premature neonates. Biol Psychiatry 87:559–569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li W, Zhang B, Tang J, Cao Q, Wu Y, Wu C, Guo J, Ling EA, Liang F (2007) Sirtuin 2, a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendroglial protein that decelerates cell differentiation through deacetylating α-tubulin. J Neurosci 27:2606–2616

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lu NZ, Cidlowski JA (2006) Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol 16:301–307

    Article  CAS  PubMed  Google Scholar 

  • Lucassen PJ, Müller MB, Holsboer F, Bauer J, Holtrop A, Wouda J, Hoogendijk WJG, de Kloet ER, Swaab DF (2001) Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol 158:453–468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma C-y, Yao M-j, Zhai Q-w, J-w J, Yuan X-b, Poo M-m (2014) SIRT1 suppresses self-renewal of adult hippocampal neural stem cells. Development 141:4697–4709

    Article  CAS  PubMed  Google Scholar 

  • MacQueen G, Frodl T (2011) The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? Mol Psychiatry 16:252–264

    Article  CAS  PubMed  Google Scholar 

  • Mirescu C, Peters JD, Gould E (2004) Early life experience alters response of adult neurogenesis to stress. Nat Neurosci 7:841–846

    Article  CAS  PubMed  Google Scholar 

  • Mohamed Ariff I, Mitra A, Basu A (2012) Epigenetic regulation of self-renewal and fate determination in neural stem cells. J Neurosci Res 90:529–539

    Article  CAS  PubMed  Google Scholar 

  • Moisiadis VG, Matthews SG (2014) Glucocorticoids and fetal programming part 1: outcomes. Nat Rev Endocrinol 10:391–402

    Article  CAS  PubMed  Google Scholar 

  • Mutsaers HA, Tofighi R (2012) Dexamethasone enhances oxidative stress-induced cell death in murine neural stem cells. Neurotox Res 22:127–137

    Article  CAS  PubMed  Google Scholar 

  • Neilson J (2007) Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Obstet Gynecol 109:189–190

    Article  PubMed  Google Scholar 

  • Peaceman A, Bajaj K, Kumar P, Grobman W (2006) The interval between a single course of antenatal steroids and delivery and its association with neonatal outcomes. Midirs Midwifery Digest 16:112–113

    Google Scholar 

  • Poulsen RC, Watts AC, Murphy RJ, Snelling SJ, Carr AJ, Hulley PA (2014) Glucocorticoids induce senescence in primary human tenocytes by inhibition of sirtuin 1 and activation of the p53/p21 pathway: in vivo and in vitro evidence. Ann Rheum Dis 73:1405–1413

    Article  CAS  PubMed  Google Scholar 

  • Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661

    Article  CAS  PubMed  Google Scholar 

  • Scheinost D, Sinha R, Cross SN, Kwon SH, Sze G, Constable RT, Ment LR (2017) Does prenatal stress alter the developing connectome? Pediatr Res 81:214–226

    Article  PubMed  Google Scholar 

  • Seckl JR (2001) Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. Mol Cell Endocrinol 185:61–71

    Article  CAS  PubMed  Google Scholar 

  • Suzuki S, Iben JR, Coon SL, Kino T (2018) SIRT1 is a transcriptional enhancer of the glucocorticoid receptor acting independently to its deacetylase activity. Mol Cell Endocrinol 461:178–187

    Article  CAS  PubMed  Google Scholar 

  • Uhlenhaut NH, Barish GD, Ruth TY, Downes M, Karunasiri M et al (2013) Insights into negative regulation by the glucocorticoid receptor from genome-wide profiling of inflammatory cistromes. Mol Cell 49:158–171

    Article  CAS  PubMed  Google Scholar 

  • Wang G, Li S, Gilbert J, Gritton HJ, Wang Z, Li Z, Han X, Selkoe DJ, Man HY (2017) Crucial roles for SIRT2 and AMPA receptor acetylation in synaptic plasticity and memory. Cell Rep 20:1335–1347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang G, Wang F, Ren J, Qiu Y, Zhang W, Gao S, Yang D, Wang Z, Liang A, Gao Z, Xu J (2018) SIRT1 involved in the regulation of alternative splicing affects the DNA damage response in neural stem cells. Cell Physiol Biochem 48:657–669

    Article  CAS  PubMed  Google Scholar 

  • Wyrwoll CS, Holmes MC, Seckl JR (2011) 11β-Hydroxysteroid dehydrogenases and the brain: from zero to hero, a decade of progress. Front Neuroendocrinol 32:265–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu D, Luo HW, Hu W, Hu SW, Yuan C, Wang GH, Zhang L, Yu H, Magdalou J, Chen LB, Wang H (2018) Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine-exposed female adult rat offspring. FASEB J 32:5563–5576

    Article  CAS  PubMed  Google Scholar 

  • Yoo DY, Kim DW, Kim MJ, Choi JH, Jung HY, Nam SM, Kim JW, Yoon YS, Choi SY, Hwang IK (2015) Sodium butyrate, a histone deacetylase inhibitor, ameliorates SIRT2-induced memory impairment, reduction of cell proliferation, and neuroblast differentiation in the dentate gyrus. Neurol Res 37:69–76

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Shang-Guan Y, Ma J, Hu H, Wang L, Magdalou J, Chen L, Wang H (2016) Mitogen-inducible gene-6 partly mediates the inhibitory effects of prenatal dexamethasone exposure on endochondral ossification in long bones of fetal rats. Br J Pharmacol 173:2250–2262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (grants 81530042, 31830059, 31721003, 31871495, 31701110) and Fundamental Research Funds for the Central Universities (22120190149).

Author information

Authors and Affiliations

  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

    Mohammed A. H. Alnoud, Wen Chen, Nana Liu, Wei Zhu, Jing Qiao, Shujuan Chang, Yukang Wu, Shanshan Wang, Yiwei Yang, Qiaoyi Sun & Jiuhong Kang

Authors
  1. Mohammed A. H. Alnoud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nana Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shujuan Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yukang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shanshan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yiwei Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qiaoyi Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jiuhong Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jiuhong Kang.

Ethics declarations

All mice were maintained and handled according to Tongji University institutional guidelines.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(DOC 121 kb)

Supplementary Figure 1.

Test of NSC proliferation by CFSE-based assay. (a) CFSE-based assay among DMSO- or DEX-treated NSCs. (b) CFSE-based assay in Sirt7-knockdown and control NSCs treated with DMSO or DEX. (c) CFSE-based assay in p21-knockdown and control NSCs treated with DMSO or DEX. (d) CFSE based-assay in shCtrl- or shSirt7 (shSirt7-1, shSirt7-2)-transfected NSCs following p21 knockdown. (e) CFSE-based assay in the DMSO+HA-Luc, DEX+HA-Luc, DEX+HA-SIRT7, DEX+HA-p21, and DEX+HA-SIRT7+HA-p21 groups. The data are shown as the mean ± SEM. Student’s t test. ***P<0.001. (JPG 706 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alnoud, M.A.H., Chen, W., Liu, N. et al. Sirt7-p21 Signaling Pathway Mediates Glucocorticoid-Induced Inhibition of Mouse Neural Stem Cell Proliferation. Neurotox Res 39, 444–455 (2021). https://doi.org/10.1007/s12640-020-00294-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-020-00294-x

Keywords

Search

Navigation