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 unique 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 brainandresulted 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.成年神经发生（adult neurogenesis）存在于哺乳动物体内，是大脑维持持续神经可塑性的重要机制。然而，目前对于调控海马神经祖细胞（neural progenitor cells, NPCs）的分子机制，以及能否通过药理学手段调控其细胞命运以改善神经可塑性与神经再生能力，尚不清楚。本研究报道了一种独特小分子化合物KHS101的表征结果，该化合物可选择性诱导神经元分化表型。作用机制研究显示，KHS101与细胞周期退出过程存在关联，并可特异性结合TACC3蛋白；在神经祖细胞中敲低TACC3的表达，能够重现KHS101诱导的表型。经全身给药后，KHS101可分布至脑部，并在体内显著提升神经元分化水平。本研究结果表明，KHS101可通过与TACC3相互作用加速神经元分化，为靶向内源性神经祖细胞的药理学干预提供了理论基础。