GSK-3 is a Master Regulator of Neural Progenitor Self-Renewal

描述(申请人提供)：在之前的资助期间，我们证明了有条件地消除胚胎神经系统中的糖原合成酶-3s(GSK-3s)α和β会导致神经前体细胞动态平衡的显著失调。这一结果具有重要的翻译意义，因为GSK-3抑制剂锂在临床实践中得到了广泛使用。我们假设，GSK-3S的失活导致祖细胞不能对细胞外信号做出反应，而细胞外信号通常调节放射状祖细胞向神经元和中间神经元前体(INPs)的转换。我们现在建议进行明确的小鼠遗传学实验，以评估这种GSK-3调控的机制(目标I和II)。此外，我们将使用化学遗传学方法来确定在GSK-3缺陷的祖细胞中重新诱导GSK-3活性是否会导致神经发生的增强(目标III)。最后，我们将询问GSK-3信号是否调节成年齿状回的神经前体(目标IV)。这项工作将揭示GSK-3调节哺乳动物神经前体细胞的功能潜力和机制。这项工作还将提供以前未被认识到的锂的潜在影响的信息。锂是一种临床常用药物，越来越多地用于儿童。最后，我们的结果可能会为在神经移植的背景下扩大神经前体种群提供新的方法。

DESCRIPTION (provided by applicant): In the prior funding period, we demonstrated that conditional elimination of the Glycogen Synthase Kinase-3s (GSK-3s), a and ¿, in the embryonic nervous system results in remarkable dysregulation of neural progenitor homeostasis. This result has important translational significance because of the widespread use of a GSK-3 inhibitor, lithium, in clinical practice. We hypothesize that inactivation of GSK-3s renders progenitors incapable of responding to the extracellular signals that normally regulate conversion of radial progenitors to neurons and intermediate neuronal precursors (INPs). We now propose definitive mouse genetic experiments to assess mechanisms of this GSK-3 regulation (Aims I and II). Further, we will use a chemical genetics approach to determine if reinduction of GSK-3 activity in GSK-3 deficient progenitors will result in enhanced neurogenesis (Aim III). Finally we will ask whether GSK-3 signaling regulates neural progenitors in the adult dentate gyrus (Aim IV). This work will reveal the functional potential and mechanisms of GSK-3 regulation of neural progenitors in mammals. The work will also provide information on previously unrecognized potential effects of lithium a drug commonly used in clinical practice, increasingly in children. Finally our results may suggest new ways to expand neural progenitor populations in the setting of neural transplantation.