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

Abstract

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 hippocampus3–5. 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 NSC 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 and Notch signaling pathways play fundamental roles during development of multicellular organisms6. In Drosophila and in C. elegans these pathways may have either cooperative or antagonistic functions7–9. In the SVZ, Notch regulates NSC identity and self-renewal, whereas EGFR specifically affects NPC proliferation and migration10–13. 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 epidermal growth factor receptor (EGFR) and Notch signaling plays a crucial role in maintaining the balance between these cell populations in the SVZ. Enhanced EGFR signaling 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 signaling. 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.

Impaired neural stem cell expansion and hypersensitivity to epileptic seizures in mice lacking the EGFR in the brain

“…In the adult brain, EGFR has been shown to play a critical role in the regulation of the neurogenic niches, found in the SVZ of the forebrain and the subgranular zone of the hippocampus 8 9 10, where activation of stem cells appears to correlate with the acquisition of EGFR expression 9. Overexpression of the EGFR in neural precursor cells has been shown to result in reduced neural stem cell proliferation and self‐renewal in the SVZ 11, illustrating a critical role of EGFR signaling not only in neural stem cell maintenance but also in astrocyte differentiation.…”

Morphological, molecular and functional differences of adult bone marrow- and adipose-derived stem cells isolated from rats of different ages

“…In vitro, differentiated adult mesenchymal stem cells show pro-liferation capacity, but it has been suggested that the therapeutic potential of stem cells, due to bioactive growth factor secretion and stimulation of neoangiogenesis, may be limited by their senes-cence, or biological aging, and by the age of the donor [8]. Recent reports indicate that aging is linked to a decline in the number of stem cells found in bone marrow aspirate [9] and of their potential to proliferate and differentiate [10][11][12].…”

“…Notch signalling seems to influ-ence important roles in many types of stem cells [8]. Adult stem cells have limited selfrenewal and proliferative potential, which decreases with the advancing age of the organism [24].…”

Temporal course of gene expression during motor memory formation in primary motor cortex of rats

“…Furthermore, it contains the mitogenic receptor tyrosine kinase Egfr that promotes neurogenesis and supports hippocampal LTP formation by influencing NMDAreceptor trafficking (Aguirre, Rubio, and Gallo, 2010;Tang, Ye, Du, Qiu, Lv, Yang, and Luo, 2015).…”