Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal

Abstract

The subventricular zone (SVZ) of the adult mammalian brain is an important site for cell proliferation, contributing to nerve-cell self-renewal and the response to injury. The SVZ stem-cell niche maintains neural stem cells (NSCs) and neural progenitor cells (NPCs), with the balance between the two being vital to normal brain development. Notch signalling is known to regulate NSC self-renewal, whereas EGFR (epidermal growth factor receptor) signalling affects NPC proliferation. Aguirre et al. show that these pathways interact to maintain a balance between NSC and NPC populations through EGFR-mediated regulation of Notch signalling. This points to specific signalling pathways that may be targeted to enhance production of NSCs or NPCs after injury. In the adult brain, neural stem cells (NSCs) and neural progenitor cells (NPCs) are maintained in the subventricular zone. There, the Notch protein regulates the identity and self-renewal of NSCs, while epidermal growth factor receptor (EGFR) affects NPC proliferation and migration. Now it is found that these signalling pathways interact to maintain the balance between NSC and NPC populations. Specialized cellular microenvironments, or ‘niches’, modulate stem cell properties, including cell number, self-renewal and fate decisions1,2. In the adult brain, niches that maintain a source of neural stem cells (NSCs) and neural progenitor cells (NPCs) are the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus of the hippocampus3,4,5. The size of the NSC population of the SVZ at any time is the result of several ongoing processes, including self-renewal, cell differentiation, and cell death. Maintaining the balance between NSCs and NPCs in the SVZ niche is critical to supply the brain with specific neural populations, both under normal conditions or after injury. A fundamental question relevant to both normal development and to cell-based repair strategies in the central nervous system is how the balance of different NSC and NPC populations is maintained in the niche. EGFR (epidermal growth factor receptor) and Notch signalling pathways have fundamental roles during development of multicellular organisms6. In Drosophila and in Caenorhabditis elegans these pathways may have either cooperative or antagonistic functions7,8,9. In the SVZ, Notch regulates NSC identity and self-renewal, whereas EGFR specifically affects NPC proliferation and migration10,11,12,13. This suggests that interplay of these two pathways may maintain the balance between NSC and NPC numbers. Here we show that functional cell–cell interaction between NPCs and NSCs through EGFR and Notch signalling has a crucial role in maintaining the balance between these cell populations in the SVZ. Enhanced EGFR signalling in vivo results in the expansion of the NPC pool, and reduces NSC number and self-renewal. This occurs through a non-cell-autonomous mechanism involving EGFR-mediated regulation of Notch signalling. Our findings define a novel interaction between EGFR and Notch pathways in the adult SVZ, and thus provide a mechanism for NSC and NPC pool maintenance.