Kageyama R, Ishibashi M, Takebayashi K, Tomita K
Department of Biological Sciences, Kyoto University Faculty of Medicine, Japan.
Int J Biochem Cell Biol. 1997 Dec;29(12):1389-99. doi: 10.1016/s1357-2725(97)89968-2.
The basic helix-loop-helix (bHLH) factor Mash1 is expressed in the developing nervous system. Null mutation of Mash1 results in loss of olfactory and autonomic neurons and delays differentiation of retinal neurons, indicating that Mash1 promotes neuronal differentiation. Other bHLH genes, Math/NeuroD/Neurogenin, all expressed in the developing nervous system, have also been suggested to promote neuronal differentiation. In contrast, another bHLH factor, HES1, which is expressed by neural precursor cells but not by neurons, represses Mash1 expression and antagonizes Mash1 activity in a dominant negative manner. Forced expression of HES1 in precursor cells blocks neuronal differentiation in the brain and retina, indicating that HES1 is a negative regulator of neuronal differentiation. Conversely, null mutation of HES1 up-regulates Mash1 expression, accelerates neuronal differentiation, and causes severe defects of the brain and eyes. Thus, HES1 regulates brain and eye morphogenesis by inhibiting premature neuronal differentiation, and the down-regulation of HES1 expression at the right time is required for normal development of the nervous system. Interestingly, HES1 can repress its own expression by binding to its promoter, suggesting that negative autoregulation may contribute to down-regulation of HES1 expression during neural development. Recent studies indicate that HES1 expression is also controlled by RBP-J, a mammalian homologue of Suppressor of Hairless [Su(H)], and Notch, a key membrane protein that may regulate lateral specification through RBP-J during neural development. Thus, the Notch-->RBP-J-->HES1-Mash1 pathway may play a critical role in neuronal differentiation.
碱性螺旋-环-螺旋（bHLH）因子Mash1在发育中的神经系统中表达。Mash1基因敲除导致嗅觉神经元和自主神经元缺失，并延迟视网膜神经元的分化，这表明Mash1促进神经元分化。其他bHLH基因，如Math/NeuroD/Neurogenin，也都在发育中的神经系统中表达，也被认为可促进神经元分化。相反，另一个bHLH因子HES1，由神经前体细胞表达而不由神经元表达，它以显性负性方式抑制Mash1表达并拮抗Mash1活性。在前体细胞中强制表达HES1会阻断大脑和视网膜中的神经元分化，这表明HES1是神经元分化的负调节因子。相反，HES1基因敲除会上调Mash1表达，加速神经元分化，并导致大脑和眼睛出现严重缺陷。因此，HES1通过抑制过早的神经元分化来调节大脑和眼睛的形态发生，神经系统的正常发育需要在适当时间下调HES1表达。有趣的是，HES1可通过结合其启动子来抑制自身表达，这表明负向自我调节可能有助于在神经发育过程中下调HES1表达。最近的研究表明，HES1表达也受RBP-J调控，RBP-J是无翅型MMTV整合位点家族成员[Su(H)]的哺乳动物同源物，以及Notch调控，Notch是一种关键的膜蛋白，在神经发育过程中可能通过RBP-J调节侧向特化。因此，Notch→RBP-J→HES1-Mash1通路可能在神经元分化中起关键作用。
