The intracellular mechanism for regulation of mammalian neural development

在哺乳动物神经发育过程中，最初维持神经前体细胞，后来分化为神经元和神经胶质细胞，形成复杂的神经系统。为了阐明神经发育的细胞内机制，我们重点研究了bHLH基因并对其功能进行了表征。由于已知维持神经前体细胞的膜蛋白Notch诱导了抑制性bHLH基因Hes1和Hes5的表达，因此首先通过在Hes1-空、Hes5-空和Hes1-Hes5双空小鼠胚胎中表达活性形式的Notch来确定这些bHLH基因在神经前体细胞中的功能。尽管Notch在缺乏Hes1或Hes5的情况下仍能抑制分化，但在缺乏Hes1和Hes5作为主要Notch效应物的情况下则不能。因此，Notch-Hes通路在神经前体细胞早期发育阶段的维持中起着重要作用。在神经发育后期，Hes5通过分化胶质细胞表达。在发育中的视网膜中，Hes5的错误表达特异性地诱导了胶质细胞的发生，相反，Hes5缺陷视网膜中的胶质细胞数量减少。相反，Hes1抑制神经元和胶质细胞的发育，甚至在后期维持神经前体细胞。神经元bHLH基因Math3和Mash1促进神经发生，抑制神经胶质瘤发生。因此，bHLH基因调节所有细胞的命运，作为前体（Hes1, Hes5）保留，并分化为神经元（Math3, Mash1）或胶质细胞（Hes5），这些bHLH基因的平衡可能对分化的时间和神经元与胶质细胞的比例很重要。

In mammalian neural development, initially neural precursor cells are maintained but later they differentiate into neurons and glial cells that form a complex nervous system. To elucidate the intracellular mechanism for neural development, we focused on bHLH genes and characterized their functions. Since the membrane protein Notch, which is known to maintain neural precursors, induced expression of the inhibitory bHLH genes Hes1 and Hes5, functions of these bHLH genes in neural precursor cells were first determined by expressing the active form of Notch in cells prepared from Hes1-null, Hes5-null, and Hes1-Hes5 double-null mouse embryos. Whereas Notch still inhibited differentiation in the absence of either Hes1 or Hes5, it did not in the absence of both Hes1 and Hes5 as essential Notch effectors. Thus, Notch-Hes pathway plays an important role in maintenance of neural precursor cells at early stages of development. At later stages of neural development, Hes5 was expressed by differentiating glial cells. Misexpression of Hes5 in the developing retina specifically induced gliogenesis and conversely glial cell number was reduced in Hes5-deficient retina. In contrast, Hes1 inhibited both neuronal and glial cell development and maintained neural precursor cells even at later stages. Neuronal bHLH genes such as Math3 and Mash1 promoted neurogenesis but inhibited gliogenesis. Thus, bHLH genes regulate all the cell fate, remaining as precursors (Hes1, Hes5) and differentiating into neurons (Math3, Mash1) or glial cells (Hes5), and the balance of these bHLH genes may be important for the timing of differentiation and the ratios of neurons versus glial cells.