Id4 Downstream of Notch2 Maintains Neural Stem Cell Quiescence in the Adult Hippocampus

Neural stem cells (NSCs) in the adult mouse hippocampal dentate gyrus (DG) are mostly quiescent, and only a few are in cell cycle at any point in time. DG NSCs become increasingly dormant with age and enter mitosis less frequently, which impinges on neurogenesis. How NSC inactivity is maintained is largely unknown. Here, we found that Id4 is a downstream target of Notch2 signaling and maintains DG NSC quiescence by blocking cell-cycle entry. Id4 expression is sufficient to promote DG NSC quiescence and Id4 knockdown rescues Notch2-induced inhibition of NSC proliferation. Id4 deletion activates NSC proliferation in the DG without evoking neuron generation, and overexpression increases NSC maintenance while promoting astrogliogenesis at the expense of neurogenesis. Together, our findings indicate that Id4 is a major effector of Notch2 signaling in NSCs and a Notch2-Id4 axis promotes NSC quiescence in the adult DG, uncoupling NSC activation from neuronal differentiation. [Display omitted] •Notch2 regulates Id4 and cell-cycle genes in hippocampal NSCs•Id4 blocks hippocampal NSC entry into cell cycle•Id4 promotes astrocytic differentiation of hippocampal NSCs•NSC activation and neuronal differentiation can be uncoupled Zhang et al. show that a Notch2-Id4 axis maintains neural stem cell quiescence in the adult hippocampus. Their study answers a central question in neural stem cell regulation in the adult dentate gyrus and identifies the mechanism for the regulation of adult neurogenesis.