Hypoxia inducible factor-1α-driven signaling networks regulating adult neurogenesis via Notch, Wnt, and MAPK pathways

The ability to detect and adapt to changes in oxygen availability is essential for survival, especially in the mammalian brain, where oxygen demand is high and tightly regulated. Hypoxia-inducible factor 1 (HIF-1) is a key transcriptional regulator of oxygen homeostasis that coordinates cellular responses to hypoxic stress. In the brain, HIF-1 is widely expressed and plays particularly important roles in neurogenic niches, where subtle variations in oxygen tension decisively influence cell fate. This narrative review systematically integrates and organizes current knowledge on the regulation of HIF-1 signaling in the brain under hypoxic conditions, with a focus on its role in mammalian neurogenesis. We highlight the temporal dynamics of HIF-1 activation and its biphasic actions following hypoxic or ischemic injury. Early activation of HIF-1 can exacerbate oxidative stress, inflammation, mitochondrial dysfunction, and neuronal apoptosis, while late activation promotes antioxidant defenses, angiogenesis, tissue repair, and neurogenesis. HIF-1α regulates the proliferation, maintenance, and differentiation of neural stem and progenitor cells through interconnected signaling pathways, such as the Wnt/β-catenin, Notch, and MAPK cascades, as well as by inducing erythropoietin and VEGF. This review provides a comprehensive framework for understanding the critical role of HIF-1 in mammalian neurogenesis and highlights future avenues for mechanistic and translational research.