组蛋白去乙酰化酶在脑发育中对神经干细胞的调控机制

Billions of neurons are generated during mammalian brain development. Remarkably, this large number of neurons are generated from a relatively small number of neural stem cells. Neural stem cells divide symmetrically to self-renew, and on the other hand, they divide asymmetrically to differentiate into neurons. This process has to be tightly controlled during brain development. Any defect in the balance between proliferation and differentiation of neural stem cells can lead to brain disorders. However, the mechanisms that regulate this balance remain to be solved. Here we use mouse models combining stem cell in vitro culture systems to investigate the mechanisms underlining the control of neural stem cells proliferation and differentiation. Particularly, we focus on how the epigenetic regulators, histone deacetylases, regulate this process. Our study will provide a systematical analysis of proliferation and differentiation of neural stem cells during brain development, which is of fundamental importance, not only for understanding brain development, but also for understanding the pathogenesis of brain disorders, and the therapeutic potentials.

哺乳动物脑中数十亿的神经元是由数目相对较少的神经干细胞分化而来。神经干细胞一方面能够通过对称性分裂进行自我更新，另一方面能够经过不对称分裂分化为神经元。神经干细胞的增殖与分化在脑发育过程中必须经过精确的调控才能维持脑的正常发育和功能发挥。如果这个过程出现缺陷，可能会导致发育性脑疾病。然而，调控神经干细胞增殖与分化的分子机制还不十分清楚。本项目将利用小鼠动物模型并结合体外干细胞培养体系，通过对组蛋白去乙酰化酶基因进行条件性敲除，研究其对神经干细胞增殖与分化调控的分子机制以及对脑发育的影响。本项目将在表观遗传调节水平进一步了解神经干细胞增殖与分化的调控机制。这项研究将有助于我们理解大脑发育过程，同时对了解脑疾病发生机理也具有重要意义。

哺乳动物大脑中有近千亿的神经元，组成了复杂的神经环路，这是大脑行使高级功能的基础。然而，这些数量庞大的神经元是由数量相对较少的神经干细胞在脑发育早期分化而来。神经元分化后迁移到皮层特定位置行使特定功能。这些过程都需要精确的调控。如果调控过程出现问题，可能会导致发育性脑疾病发生。因此，研究神经干细胞如何分化生成神经元以及神经元分化后如何迁移到皮层特定位置具有重要意义。表观遗传调控是神经干细胞增殖分化的重要调控机制。本项目以小鼠为动物模型，结合分子生物学、生物化学和细胞学技术，研究了神经干细胞子代命运决定机制以及神经元迁移定位机制。我们发现1）神经元中间前体细胞在皮层中的精确定位是皮层发育的关键；2）神经元前体细胞迁移在海马发育过程中发挥重要作用；3）神经元在皮层中的定位是神经元环路功能建立的基础。这些研究不仅加深了我们对脑发育的理解，也为进一步解析脑疾病机理奠定重要基础。