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

描述（由申请人提供）：在先前的资助期内，我们证明了胚胎神经系统中糖原合成酶激酶-3s（GSK-3s）a和<$的条件性消除会导致神经祖细胞稳态的显著失调。由于GSK-3抑制剂锂在临床实践中的广泛使用，该结果具有重要的转化意义。我们假设GSK-3的失活使祖细胞不能响应细胞外信号，这些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）的转化。我们现在提出确定的小鼠遗传实验，以评估GSK-3调节的机制（目的I和II）。此外，我们将使用化学遗传学方法来确定GSK-3缺陷祖细胞中GSK-3活性的再诱导是否会导致增强的神经发生（Aim III）。最后，我们将询问GSK-3信号传导是否调节成年齿状回中的神经祖细胞（Aim IV）。这项工作将揭示GSK-3对哺乳动物神经前体细胞的功能潜力和调控机制。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，锂是临床实践中常用的药物，越来越多地用于儿童。最后，我们的研究结果可能会提出新的方法来扩大神经祖细胞群体的设置神经移植。 公共卫生相关性：我们提出一种特定的蛋白质GSK-3是神经干细胞的主要调节剂。GSK-3的这种功能需要研究，因为GSK-3抑制剂锂通常用于临床实践，越来越多地用于儿童。我们的研究结果也可能为在神经移植中扩增神经干细胞提供新的方法

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. PUBLIC HEALTH RELEVANCE: We propose that a specific protein, GSK-3, is a master regulator of neural stem cells. This function of GSK-3 requires investigation because a GSK-3 inhibitor, lithium, is commonly used in clinical practice, increasingly in children. Our results may also suggest new ways to expand neural stem cells in the setting of neural transplantation