Histone Deacetylase Inhibition Mediates Urocortin-Induced Antiproliferation and Neuronal Differentiation in Neural Stem Cells§

Authors

  • Hsin-Yi Huang,

    1. Department of Medical Research, Neuro-Medical Scientific Center, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
    2. Institute of Medical Science, Buddhist Tzu Chi University, Hualien, Taiwan
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  • Demeral D. Liu,

    1. Department of Dentistry and Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
    2. Department of Dentistry, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
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  • Hui-Fen Chang,

    1. Department of Medical Research, Neuro-Medical Scientific Center, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
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  • Wu-Fu Chen,

    1. Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
    2. Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung, Taiwan
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  • Hui-Ru Hsu,

    1. Department of Medical Research, Neuro-Medical Scientific Center, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
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  • Jon-Son Kuo,

    1. Institute of Medical Science, Buddhist Tzu Chi University, Hualien, Taiwan
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  • Mei-Jen Wang

    Corresponding author
    1. Department of Medical Research, Neuro-Medical Scientific Center, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
    2. Institute of Medical Science, Buddhist Tzu Chi University, Hualien, Taiwan
    • Department of Medical Research, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan
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    • Telephone: 886-3-856-1825, ext. 5616; Fax: 886-3-856-2019;


  • 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.

Abstract

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

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