Maintenance of neural stem cells in the brain: Role of notch signaling

Abstract

Activation of the transmembrane protein Notch by its ligands such as Deltalike1 (Dll1) releases the intracellular domain of Notch, which forms a complex with the DNA-binding protein Rbpj. This complex then induces expression of the transcriptional repressor gene Hes1 and its related genes. Hes genes regulate maintenance of neural stem/progenitor cells by repressing proneural gene expression. In the absence of Rbpj or Hes genes, proneural gene expression is up-regulated, leading to premature formation of neurons and depletion of neural stem/progenitor cells. In neural stem/progenitor cells, Hes1 expression oscillates with a period of 2-3 h by negative feedback, and this Hes1 oscillation induces the oscillatory expression of the proneural gene Neurogenin2 (Ngn2) and the Notch ligand gene Dll1. Dll1 oscillation then activates Notch signaling between neural stem/progenitor cells, thereby maintaining the undifferentiated state. After Hes1 expression is repressed, Ngn2 is expressed in a sustained manner, promoting neuronal differentiation. In the adult brain, neural stem cells are in two regions, the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus. Neurogenesis occurs continuously in these regions and plays an important role in brain function. In the absence of Rbpj, the proneural gene Mash1 is up-regulated, and all neural stem cells differentiate into neurons. As a result, neurogenesis is enhanced transiently, but neural stem cells are depleted and neurogenesis ceases prematurely. Thus, Notch signaling is essential for maintenance of neural stem cells and continuous neurogenesis in both embryonic and adult brains.