A small molecule accelerates neuronal differentiation in the adult rat

作者：Wurdak Heiko; Zhu Shoutian; Min Kyung Hoon; Aimone Lindsey; Lairson Luke L; Watson James; Chopiuk Gregory; Demas James; Charette Bradley; 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^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(38): 16542-16547.

DOI：10.1073/pnas.1010300107

• adult neurogenesis
• neural progenitor cell
• Tacc3

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.

• 出版日期2010-9-21