Hiroshi Kanno, Kimihiro Nakahara
The von Hippel-Lindau (VHL) protein, traditionally known for oxygen sensing via HIF-1α degradation, is now recognized as a multifunctional regulator of neural stem cell (NSC) fate and central nervous system regeneration. This review examines VHL's role in lineage specification and its therapeutic potential. Under normoxia, VHL promotes rapid neuronal differentiation by suppressing JAK2/STAT and Notch signaling pathways. This relief of repression activates proneural bHLH factors like Neurogenin2 and Ascl1, leading to the generation of electrophysiologically mature, MAP2-positive neurons. Conversely, hypoxia-induced HIF-1α stabilization biases NSCs toward a glial fate, supporting survival and astrocytic differentiation in the injured environment. Beyond its canonical role, specialized modules expand VHL's utility: The transferable BC-box motif can independently induce neuronal commitment in various somatic stem cells, while the Daam2-VHL-Nedd4 axis supports oligodendrocyte maturation and remyelination. Translational studies in models of Parkinson's disease and spinal cord injury demonstrate that VHL-based strategies can achieve significant functional recovery. Understanding the context-dependent dynamics of VHL signaling is crucial for advancing regenerative therapies for neurodegenerative and demyelinating disorders.