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A small molecule accelerates neuronal differentiation in the adult rat

Academic Article
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Overview

authors

  • Wurdak, H.
  • Zhu, S.
  • Min, K. H.
  • Aimone, L.
  • Lairson, Luke
  • Watson, J.
  • Chopiuk, G.
  • Demas, J.
  • Charette, B.
  • Weerapana, E.
  • Cravatt, Benjamin
  • Cline, Hollis
  • Zhang, J.
  • Peters, E. C.
  • Walker, J. R.
  • Chang, J.
  • Wu, Chunlei
  • Tuntland, T.
  • Cho, C. Y.
  • Schultz, Peter

publication date

  • 2010

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Adult neurogenesis occurs in mammals and provides a mechanism for continuous neural plasticity in the brain. However, little is known about the molecular mechanisms regulating hippocampal neural progenitor cells (NPCs) and whether their fate can be pharmacologically modulated to improve neural plasticity and regeneration. Here, we report the characterization of a small molecule (KHS101) that selectively induces a neuronal differentiation phenotype. Mechanism of action studies revealed a link of KHS101 to cell cycle exit and specific binding to the TACC3 protein, whose knockdown in NPCs recapitulates the KHS101-induced phenotype. Upon systemic administration, KHS101 distributed to the brain and resulted in a significant increase in neuronal differentiation in vivo. Our findings indicate that KHS101 accelerates neuronal differentiation by interaction with TACC3 and may provide a basis for pharmacological intervention directed at endogenous NPCs.

subject areas

  • Adult Stem Cells
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Hippocampus
  • Male
  • Neurogenesis
  • Neurons
  • Phenotype
  • RNA, Messenger
  • Rats
  • Rats, Inbred F344
  • Rats, Sprague-Dawley
  • Thiazoles
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Identity

PubMed Central ID

  • PMC2944756

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1010300107

PubMed ID

  • 20823227
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Additional Document Info

start page

  • 16542

end page

  • 16547

volume

  • 107

issue

  • 38

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