EGFR Signaling Termination via Numb Trafficking in Ependymal Progenitors Controls Postnatal Neurogenic Niche Differentiation

Abstract

Summary: Specialized microenvironments, called niches, control adult stem cell proliferation and differentiation. The brain lateral ventricular (LV) neurogenic niche is generated from distinct postnatal radial glial progenitors (pRGPs), giving rise to adult neural stem cells (NSCs) and niche ependymal cells (ECs). Cellular-intrinsic programs govern stem versus supporting cell maturation during adult niche assembly, but how they are differentially initiated within a similar microenvironment remains unknown. Using chemical approaches, we discovered that EGFR signaling powerfully inhibits EC differentiation by suppressing multiciliogenesis. We found that EC pRGPs actively terminated EGF activation through receptor redistribution away from CSF-contacting apical domains and that randomized EGFR membrane targeting blocked EC differentiation. Mechanistically, we uncovered spatiotemporal interactions between EGFR and endocytic adaptor protein Numb. Ca2+-dependent basolateral targeting of Numb is necessary and sufficient for proper EGFR redistribution. These results reveal a previously unknown cellular mechanism for neighboring progenitors to differentially engage environmental signals, initiating adult stem cell niche assembly. : Constructing adult stem niches from postnatal progenitors requires differential cellular interpretations of similar microenvironmental signals. Abdi et al. show that in an EGF-rich environment needed for adult neural stem cell proliferation, a subpopulation of postnatal progenitors downregulates EGFR signaling via targeted receptor trafficking, promoting multiciliated ependymal niche cell differentiation. Keywords: ependymal cells, neurogenic niche, radial glia, Numb, EGFR, Foxj1, receptor trafficking, multiciliated differentiation, hydrocephalus