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首页> 外文期刊>Biology Open >Regulation of differentiation flux by Notch signalling influences the number of dopaminergic neurons in the adult brain
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Regulation of differentiation flux by Notch signalling influences the number of dopaminergic neurons in the adult brain

机译：Notch信号对分化通量的调节影响成年大脑中多巴胺能神经元的数量

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Notch signalling is a well-established pathway that regulates neurogenesis. However, little is known about the role of Notch signalling in specific neuronal differentiation. Using Dll1 null mice, we found that Notch signalling has no function in the specification of mesencephalic dopaminergic neural precursor cells (NPCs), but plays an important role in regulating their expansion and differentiation into neurons. Premature neuronal differentiation was observed in mesencephalons of Dll1 -deficient mice or after treatment with a Notch signalling inhibitor. Coupling between neurogenesis and dopaminergic differentiation was indicated from the coincident emergence of neuronal and dopaminergic markers. Early in differentiation, decreasing Notch signalling caused a reduction in NPCs and an increase in dopaminergic neurons in association with dynamic changes in the proportion of sequentially-linked dopaminergic NPCs (Msx1/2+, Ngn2+, Nurr1+). These effects in differentiation caused a significant reduction in the number of dopaminergic neurons produced. Accordingly, Dll1 haploinsufficient adult mice, in comparison with their wild-type littermates, have a consistent reduction in neuronal density that was particularly evident in the substantia nigra pars compacta. Our results are in agreement with a mathematical model based on a Dll1-mediated regulatory feedback loop between early progenitors and their dividing precursors that controls the emergence and number of dopaminergic neurons.
机译：Notch信号传导是调节神经发生的公认途径。但是，关于Notch信号在特定神经元分化中的作用知之甚少。使用Dll1空小鼠，我们发现Notch信号在中脑多巴胺能神经前体细胞（NPC）的规范中没有功能，但在调节其扩展和分化为神经元中起重要作用。在Dll1缺陷小鼠的中脑中或用Notch信号抑制剂治疗后，观察到过早的神经元分化。神经发生和多巴胺能标记的同时出现表明了神经发生和多巴胺能分化之间的耦合。在分化的早期，Notch信号的减少导致NPC的减少和多巴胺能神经元的增加，以及顺序连接的多巴胺能NPC（Msx1 / 2 +，Ngn2 +，Nurr1 +）比例的动态变化。分化中的这些作用导致产生的多巴胺能神经元数量的显着减少。因此，与野生型同窝幼仔相比，Dll1单倍体不足的成年小鼠的神经元密度持续降低，这在黑质致密部特别明显。我们的结果与基于模型的模型相吻合，该模型基于Dll1介导的早期祖细胞与其分裂前体之间的调节反馈回路，该回路控制多巴胺能神经元的出现和数量。

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