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PMID: 20823227 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A small molecule accelerates neuronal differentiation in the adult rat.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 107 ·No. 38 ·2010-09-21 ·Pages 16542-7

Wurdak H, Zhu S, Min KH, Aimone L, Lairson LL, Watson J, Chopiuk G, Demas J, Charette B, Halder R, Weerapana E, Cravatt BF, Cline HT, Peters EC, Zhang J, Walker JR, Wu C, Chang J, Tuntland T, Cho CY, Schultz PG

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.

MeSH Terms
Adult Stem Cells/cytology,drug effects Animals Basic Helix-Loop-Helix Transcription Factors/genetics Cell Cycle/drug effects Cell Differentiation/drug effects Cell Proliferation/drug effects Cells, Cultured Hippocampus/cytology Male Neurogenesis/drug effects Neurons/cytology,drug effects,metabolism Phenotype RNA, Messenger/genetics,metabolism Rats Rats, Inbred F344 Rats, Sprague-Dawley Thiazoles/chemistry,pharmacokinetics,pharmacology
Chemicals
Basic Helix-Loop-Helix Transcription Factors KHS101 Neurod1 protein, rat RNA, Messenger Thiazoles
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Wurdak Heiko
The Skaggs Institute of Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Zhu Shoutian
Min Kyung Hoon
Aimone Lindsey
Lairson Luke L
Watson James
Chopiuk Gregory
Demas James
Charette Bradley
Halder Rajkumar
Weerapana Eranthie
Cravatt Benjamin F
Cline Hollis T
Peters Eric C
Zhang Jay
Walker John R
Wu Chunlei
Chang Jonathan
Tuntland Tove
Cho Charles Y
Schultz Peter G
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1010300107
Published
2010-09-21
Epub
2010-00-07
Pages
16542-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2944756
Subset
IM
Grants
NEI NIH HHS · R01 EY011261 · United States
NCI NIH HHS · R37 CA087660 · United States
CIHR · Canada
Databases
GEO
GSE23668
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1073/pnas.1010300107 PMC Full Text View journal details
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