title: A small molecule accelerates neuronal differentiation in the adult rat.
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.
authors.affiliation: The Skaggs Institute of Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Heiko
authors.initials: H
authors.lastname: Wurdak
authors.forename: Shoutian
authors.initials: S
authors.lastname: Zhu
authors.forename: Kyung Hoon
authors.initials: KH
authors.lastname: Min
authors.forename: Lindsey
authors.initials: L
authors.lastname: Aimone
authors.forename: Luke L
authors.initials: LL
authors.lastname: Lairson
authors.forename: James
authors.initials: J
authors.lastname: Watson
authors.forename: Gregory
authors.initials: G
authors.lastname: Chopiuk
authors.forename: James
authors.initials: J
authors.lastname: Demas
authors.forename: Bradley
authors.initials: B
authors.lastname: Charette
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Halder
authors.forename: Eranthie
authors.initials: E
authors.lastname: Weerapana
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Hollis T
authors.initials: HT
authors.lastname: Cline
authors.forename: Eric C
authors.initials: EC
authors.lastname: Peters
authors.forename: Jay
authors.initials: J
authors.lastname: Zhang
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: Chunlei
authors.initials: C
authors.lastname: Wu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chang
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Cho
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
mesh_terms: 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*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012333:RNA, Messenger; D013844:Thiazoles; C553183:KHS101; C490555:Neurod1 protein, rat
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