DISTINCT ROLES OF HIF1A AND HIF2A AT PRIMARY CILIA IN NEURONAL CELLS

Primary cilia are centrosome-derived sensory organelles that function as key mediators of extracellular signal detection and integration and are present on nearly all mammalian cell types. Within the central nervous system, they play an essential role in maintaining neuroplasticity. Recent studies have shown a functional dependence of primary cilia on HIF2a during cellular adaptation to hypoxia. The aim of this study was to further elucidate the role of hypoxia-inducible factors (HIFs) in the context of primary cilia. In the first part of the study, a ciliary, proteasomally processed variant of HIF2a with a molecular weight of approximately 66 kDa was identified following isolation of primary cilia from SH-SY5Y cells. Proteasome inhibition prevented hypoxia-induced elongation of primary cilia, indicating that proteasomal regulation is essential for ciliary HIF2a function. The second part focused on the previously unknown relationship between primary cilia and HIF1a. A Hif1a knockout was generated using a Cre/LoxP system and validated by Western blot and qPCR analyses. Loss of HIF1a resulted in significant changes in the expression of cilia-associated signaling components. Notably, NeuroD1 and Sav1 expression was increased, accompanied by enhanced neuronal differentiation, reduced proliferation, and increased ciliarization. In conclusion, this study demonstrates distinct, cilia-specific functions of HIF1a and HIF2a and underscores the importance of primary cilia in hypoxic signal transduction. Further studies are required to determine whether these mechanisms are specific to the central nervous system or represent a general cellular principle.