Reactive Oxygen Species Signaling Promotes Hypoxia-Inducible Factor 1α Stabilization in Sonic Hedgehog-Driven Cerebellar Progenitor Cell Proliferation

• Published in: Molecular and cellular biology 2019-04, Vol.39 (8)
• Main Authors: Eyrich, Nicholas W., Potts, Chad R., Robinson, M. Hope, Maximov, Victor, Kenney, Anna M.
• Format: Article
• Language: English
• Subjects: Animals; Cell Proliferation - physiology; Cells, Cultured; Cerebellar Neoplasms; Cerebellum - cytology; Cerebellum - metabolism; Female; Hedgehog Proteins - metabolism; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; hypoxia-inducible factor 1a; Male; medulloblastoma; Mice; NADPH Oxidases - metabolism; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurons - cytology; Neurons - metabolism; reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction; Sonic Hedgehog; stem cells; Stem Cells - cytology; Stem Cells - metabolism
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.00268-18

Cerebellar development is a highly regulated process involving numerous factors acting with high specificity, both temporally and by location. Part of this process involves extensive proliferation of cerebellar granule neuron precursors (CGNPs) induced by Sonic Hedgehog (SHH) signaling, but downstream effectors of mitogenic signaling are still being elucidated. Using primary CGNP cultures, a well-established model for SHH-driven proliferation, we show that SHH-treated CGNPs feature high levels of hypoxia-inducible factor 1α (HIF1α), which is known to promote glycolysis, stemness, and angiogenesis. In CGNPs cultured under normoxic conditions, HIF1α is posttranslationally stabilized in a manner dependent upon reactive oxygen species (ROS) and NADPH oxidase (NOX), both of which are also upregulated in these cells. Inhibition of NOX activity resulted in HIF1α destabilization and reduced levels of cyclin D2, a marker of CGNP proliferation. As CGNPs are the putative cells of origin for the SHH subtype of medulloblastoma and aberrant SHH signaling is implicated in other neoplasms, these studies may also have future relevance in the context of cancer. Taken together, our findings suggest that a better understanding of nonhypoxic HIF1α stabilization through NOX-induced ROS generation can provide insights into normal cell proliferation in cerebellar development and SHH-driven cell proliferation in cancers with aberrant SHH signaling.