Dual Role of Rbpj in the Maintenance of Neural Progenitor Cells and Neuronal Migration in Cortical Development

Abstract

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.