Notch-dependent mechanistic strategies for stem cell maintenance and differentiation. (A) Neuronal differentiation in the developing neuroepithelium is dependent on an asymmetric cell division in which Numb is asymmetrically distributed and inhibits Notch signaling in one of the cells to permit neuronal differentiation. (B) In the developing brain, Notch controls the oscillation of downstream genes (hes1 and Ngn2) that allows controlled proliferation and differentiation waves in the midbrain compartment. In the boundary (green boxes), Hes1 protein levels are sustained, Ngn2 levels are low, and proliferation and neuron formation are inhibited.¹⁴¹  (C) Notch promotes cell proliferation in the basal layer of the embryonic epidermis, however, in adult epidermis. (D) Notch is inhibiting proliferation and inducing differentiation of the interfollicular basal layer. In the bulge, Notch and Jag1 are regulating epidermal stem cells by promoting the follicular stem cell fate downstream of Wnt/β-catenin. (E) Two types of ISCs have been identified: Lgr5⁺ proliferating cells and quiescent +4 cells (Bmi⁺). Lgr5⁺ cells are located at the bottom of the intestinal crypts, next to an intestinal secretory-type cell called Paneth cell. These cells are crucial ISC-niche elements, express Notch-ligands Dll1 and Dll4, and are required to maintain ISCs (probably through Notch activation). However, differentiation to the secretory lineage, including Paneth cells, requires Atonal, which is a target of Notch/hes1 repression, suggesting that generation of the ISC niche is under the control of ISCs through Notch. (F) Notch signaling induced by Delta1 is required for muscle regeneration on injury. The balance between Notch and TGFb/smad3 signals determines the levels of CDK inhibitors and the proliferative capacity of muscle progenitors.