PRIMARY CILIA AS HYPOXIA-SENSITIVE SIGNALING HUBS OF NEURONAL COMMUNICATION AND BRAIN REGENERATION

Primary cilia are microtubule-based organelles that function as sensory hubs, translating extracellular cues into intracellular responses. Through signaling pathways such as Shh, Notch, and TGF-β, they regulate fundamental cellular processes including proliferation and migration. Proper ciliary function depends on structural integrity, which is maintained in part by intraflagellar transport (IFT). Disruption of ciliary signaling leads to a group of disorders known as ciliopathies, frequently associated with malformations of the central nervous system. Altered cilia length is a common indicator of impaired ciliary function.
During hypoxic conditions, such as those occurring in ischemic stroke, rapid and precise signal regulation is essential for cellular adaptation and survival. Central mediators of the hypoxic response are hypoxia-inducible factors (HIFs). In particular, HIF-2 plays a key role in promoting neurogenesis and protecting neuronal stem cells, making it highly relevant for the regeneration of cerebral injuries.
Our study demonstrates that hypoxia-inducible factor-2α (HIF-2α) localizes to the axoneme of primary cilia in neuronal cells and induces axonemal elongation through direct interaction with the IFT protein IFT88. Furthermore, activation of the MEK/ERK signaling pathway and downstream gene expression occurs only when primary cilia are intact and HIF-2α is accumulated in the ciliary axoneme. These findings indicate that ciliary HIF-2 signaling supports regenerative processes involved in cellular recovery.
Overall, this work highlights primary cilia as critical regulators of cellular responses to hypoxic stress and encourages further investigation into additional ciliary structures, such as the specialized ciliary proteasome, whose potential involvement in HIF signaling under hypoxia remains largely unexplored.