EphB受体信号介导的神经干细胞分化机制

Neural stem cells (NSCs) are able to differentiate into multiple neural cell types including neurons and glias. In adult brain, NSCs are localized and differentiated into new neurons within the subventricular zone (SVZ ) of lateral ventricles and the dentate gyrus of the hippocampus (subgranular zone, SGZ), which are critical for both maintaining/renewing of neural circuits in normal physiological conditions and recovery of neural function in pathological conditions. Therefore, it is an important question to investigate the in vivo mechanisms for production and differentiation of NSC as well as integration of neural function. Eph receptor kinases are one of the largest membrane expressed receptor families. Among the receptor members, EphB receptors are highly expressed in NSC and may mediate their self-renewing, migration, differentiation and linage plasticity via regulating intracellular signal transduction, but the underlying mechanism remains unclear. The proposed studies aims to clarify the mechanism for NSC development and differentiation by using a series of Eph/ephrin knockout/knockin mice combined with stem cell biology, histology and biochemistry. The study should lead to an increased understanding of new mechanisms for neural circuit formation and maintaining, which will provide novel therapeutic targets and therapeutic methods for diseases of brain injury.

神经干细胞具有发育成神经元细胞和神经胶质细胞等多种神经细胞的能力。成年动物的脑中海马齿状回的颗粒下层（SGZ）和侧脑室下层（SVZ）存在神经干细胞，这些神经干细胞的存在和发育，对于神经环路的维持和更新，以及病理状态下的神经功能的恢复至关重要。因此，研究调节神经干细胞的产生，分化及神经功能整合的体内机制成为一个至关重要的科学问题。Eph 酪氨酸激酶受体是一类高度表达于神经细胞膜上的受体家族，其中的EphB在脑中的神经干细胞中大量表达，可能通过调控细胞内的一些信号因子，调节神经干细胞的增殖、迁移、分化和谱系可塑性，但是其作用机制尚不清楚。本课题我们将以EphB2基因敲除和突变的小鼠为基础，结合干细胞生物学、组织形态学和生物化学等方法，探讨神经干细胞发育和分化机制，加深对大脑神经环路功能的形成和维持的理解，为脑疾病如脑损伤的有效处理和治疗提供新的思路和策略。

海马区成年神经干细胞通过神经发生产生新生神经元并整合到神经环路中，这些新生神经元对于学习记忆起到至关重要的作用。神经干细胞静息态的维持和神经发生的调控机制目前依然不十分清楚。大量研究表明神经干细胞静息态是受到其所处的干细胞微环境调控的。神经干细胞通过其细胞膜表面的受体分子接受外界信号，调控其维持静息和分化。我们在本项目中发现，神经细胞膜表面的受体酪氨酸激酶受体EphB表达在成年海马神经干细胞中并参与神经干细胞静息态以及神经发生的调控过程。阻断EphB2信号使静息态神经干细胞被大量激活，产生过多的新生神经元。通过细胞与细胞的接触，神经干细胞EphB2信号受到其周围神经元上的ephrin-B3激活。我们进一步发现膜蛋白EphB2是通过影响胞内分子PTEN入核发挥对神经发生的调节作用。这些结果提示ephrin-B3-EphB2-PTEN介导信号在海马区成年神经干细胞的静息态以及神经发生的调控起到了关键作用。