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Tissue-Specific Stem Cells
Version of Record online: 27 NOV 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 12, pages 2760–2773, December 2012
How to Cite
Huang, H.-Y., Liu, D. D., Chang, H.-F., Chen, W.-F., Hsu, H.-R., Kuo, J.-S. and Wang, M.-J. (2012), Histone Deacetylase Inhibition Mediates Urocortin-Induced Antiproliferation and Neuronal Differentiation in Neural Stem Cells. STEM CELLS, 30: 2760–2773. doi: 10.1002/stem.1226
Author contributions: H.-Y.H.: collection and/or assembly of data, data analysis and interpretation, and manuscript writing; D.D.L.: collection and/or assembly of data and data analysis and interpretation; H.-F.C., W.-F.C., and H.-R.H.: collection and/or assembly of data; J.-S.K.: final approval of manuscript; M.-J.W.: financial support, conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript. H.-Y.H and D.D.L contributed equally to this article.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS September 7, 2012.
- Issue online: 27 NOV 2012
- Version of Record online: 27 NOV 2012
- Accepted manuscript online: 7 SEP 2012 01:04PM EST
- Manuscript Accepted: 14 AUG 2012
- Manuscript Received: 21 MAR 2012
- NSC 98-2320-B-303-003-MY3
- Histone deacetylase;
- Neural stem cells;
During cortical development, cell proliferation and cell cycle exit are carefully regulated to ensure that the appropriate numbers of cells are produced. Urocortin (UCN) is a member of the corticotrophin releasing hormone (CRH) family of neuropeptides that regulates stress responses. UCN is widely distributed in adult rat brain. However, the expression and function of UCN in embryonic brain is, as yet, unclear. Here, we show that UCN is endogenously expressed in proliferative zones of the developing cerebral cortex and its receptors are exhibited in neural stem cells (NSCs), thus implicating the neuropeptide in cell cycle regulation. Treatment of cultured NSCs or organotypic slice cultures with UCN markedly reduced cell proliferation. Furthermore, blocking of endogenous UCN/CRHRs system either by treatment with CRHRs antagonists or by neutralization of secreted UCN with anti-UCN antibody increased NSCs proliferation. Cell cycle kinetics analysis demonstrated that UCN lengthened the total cell cycle duration via increasing the G1 phase and accelerated cell cycle exit. UCN directly inhibited the histone deacetylase (HDAC) activity and induced a robust increase in histone H3 acetylation levels. Using pharmacological and RNA interference approaches, we further demonstrated that antiproliferative action of UCN appeared to be mediated through a HDAC inhibition-induced p21 upregulation. Moreover, UCN treatment in vitro and in vivo led to an increase in neuronal differentiation of NSCs. These findings suggest that UCN might contribute to regulate NSCs proliferation and differentiation during cortical neurogenesis. STEM CELLS 2012;30:2760–2773