A small molecule accelerates neuronal differentiation in the adult rat.
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.
Wurdak
Heiko
H
The Skaggs Institute of Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Zhu
Shoutian
S
Min
Kyung Hoon
KH
Aimone
Lindsey
L
Lairson
Luke L
LL
Watson
James
J
Chopiuk
Gregory
G
Demas
James
J
Charette
Bradley
B
Halder
Rajkumar
R
Weerapana
Eranthie
E
Cravatt
Benjamin F
BF
Cline
Hollis T
HT
Peters
Eric C
EC
Zhang
Jay
J
Walker
John R
JR
Wu
Chunlei
C
Chang
Jonathan
J
Tuntland
Tove
T
Cho
Charles Y
CY
Schultz
Peter G
PG
D053687:Adult Stem Cells / Q000166:cytology / Q000187:drug effects; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology; D008297:Male; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D051792:Basic Helix-Loop-Helix Proteins; D012333:RNA, Messenger; D013844:Thiazoles; C553183:KHS101; C490555:Neurod1 protein, rat
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