The study investigates the role of Notch signaling in regulating stem cell numbers both in vitro and in vivo. Notch receptor activation induces the expression of target genes such as Hes3 and Shh, promoting neural stem cell survival through rapid activation of cytoplasmic signals including Akt, STAT3, and mTOR. In murine somatic and human embryonic stem cells, these positive signals are counteracted by a control mechanism involving p38 mitogen-activated protein kinase. Transient administration of Notch ligands to the brain of adult rats increases the number of newly generated precursor cells and improves motor skills after ischemic injury. These findings suggest that Notch ligands may be used to expand stem cells in vitro and in vivo, potentially leading to new strategies for regenerative medicine. The study also highlights the importance of cytoplasmic functions of the Notch receptor in regulating the Hes/Hey gene family and the role of p38 in antagonizing Notch signaling.The study investigates the role of Notch signaling in regulating stem cell numbers both in vitro and in vivo. Notch receptor activation induces the expression of target genes such as Hes3 and Shh, promoting neural stem cell survival through rapid activation of cytoplasmic signals including Akt, STAT3, and mTOR. In murine somatic and human embryonic stem cells, these positive signals are counteracted by a control mechanism involving p38 mitogen-activated protein kinase. Transient administration of Notch ligands to the brain of adult rats increases the number of newly generated precursor cells and improves motor skills after ischemic injury. These findings suggest that Notch ligands may be used to expand stem cells in vitro and in vivo, potentially leading to new strategies for regenerative medicine. The study also highlights the importance of cytoplasmic functions of the Notch receptor in regulating the Hes/Hey gene family and the role of p38 in antagonizing Notch signaling.