Abstract

The development of the cerebral cortex is directed by a series of methodically precise events, including progenitor cell proliferation, neural differentiation, and cell positioning. Over the past decade, many studies have demonstrated the critical contributions of Notch signaling in neurogenesis, including that in the developing telencephalon. However, in vivo evidence for the role of Notch signaling in cortical development still remains limited partly due to the redundant functions of four mammalian Notch paralogues and embryonic lethality of the knockout mice. Here, we utilized the conditional deletion and in vivo gene manipulation of Rbpj, a transcription factor that mediates signaling by all four Notch receptors, to overcome these challenges and examined the specific roles of Rbpj in cortical development. We report severe structural abnormalities in the embryonic and postnatal cerebral cortex in Rbpj conditional knockout mice, which provide strong in vivo corroboration of previously reported functions of Notch signaling in neural development. Our results also provide evidence for a novel dual role of Rbpj in cell type-specific regulation of two key developmental events in the cerebral cortex: the maintenance of the undifferentiated state of neural progenitor cells, and the radial and tangential allocation of neurons, possibly through stage-dependent differential regulation of Ngn1.

中文翻译：

---

Rbpj 在维持神经祖细胞和皮质发育中的神经元迁移中的双重作用。

摘要

大脑皮层的发育由一系列有条不紊的精确事件指导，包括祖细胞增殖、神经分化和细胞定位。在过去的十年中，许多研究证明了 Notch 信号在神经发生中的重要贡献，包括在发育中的端脑。然而，由于四种哺乳动物 Notch 旁系同源基因的冗余功能和敲除小鼠的胚胎致死率，Notch 信号在皮质发育中的作用的体内证据仍然有限。在这里，我们利用Rbpj的条件缺失和体内基因操作，Rbpj是一种介导所有四种 Notch 受体信号传导的转录因子，以克服这些挑战并检查Rbpj的具体作用在皮质发育中。我们报告了Rbpj条件敲除小鼠胚胎和出生后大脑皮层的严重结构异常，这为先前报告的 Notch 信号在神经发育中的功能提供了强有力的体内证实。我们的研究结果还为Rbpj在大脑皮层两个关键发育事件的细胞类型特异性调节中的新双重作用提供了证据：维持神经祖细胞的未分化状态，以及神经元的径向和切向分配，可能通过Ngn1 的阶段依赖性差异调节。