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

描述（由申请人提供）：在之前的资助期内，我们证明了胚胎神经系统中糖原合成酶激酶3 (gsk -3)， a和¿的条件消除会导致神经祖细胞稳态的显着失调。由于GSK-3抑制剂锂在临床实践中的广泛应用，该结果具有重要的翻译意义。我们假设GSK-3s的失活使祖细胞无法响应细胞外信号，而细胞外信号通常调节径向祖细胞向神经元和中间神经元前体（INPs）的转化。我们现在提出明确的小鼠遗传实验来评估GSK-3调控的机制（目的1和目的2）。此外，我们将使用化学遗传学方法来确定在GSK-3缺陷祖细胞中重新诱导GSK-3活性是否会导致神经发生增强（Aim III）。最后，我们将询问GSK-3信号是否调节成人齿状回中的神经祖细胞（Aim IV）。本研究将揭示GSK-3调控哺乳动物神经祖细胞的功能潜力及其机制。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，锂是一种临床实践中常用的药物，越来越多地用于儿童。最后，我们的结果可能为在神经移植的背景下扩大神经祖细胞群提供新的途径。

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.