Interaction of hypoxia-inducible factor-1α and Notch signaling regulates medulloblastoma precursor proliferation and fate

Stem Cells. 2010 Nov;28(11):1918-29. doi: 10.1002/stem.518.


Medulloblastoma (MDB) is the most common brain malignancy of childhood. It is currently thought that MDB arises from aberrantly functioning stem cells in the cerebellum that fail to maintain proper control of self-renewal. Additionally, it has been reported that MDB cells display higher endogenous Notch signaling activation, known to promote the survival and proliferation of neoplastic neural stem cells and to inhibit their differentiation. Although interaction between hypoxia-inducible factor-1α (HIF-1α) and Notch signaling is required to maintain normal neural precursors in an undifferentiated state, an interaction has not been identified in MDB. Here, we investigate whether hypoxia, through HIF-1α stabilization, modulates Notch1 signaling in primary MDB-derived cells. Our results indicate that MDB-derived precursor cells require hypoxic conditions for in vitro expansion, whereas acute exposure to 20% oxygen induces tumor cell differentiation and death through inhibition of Notch signaling. Importantly, stimulating Notch1 activation with its ligand Dll4 under hypoxic conditions leads to expansion of MDB-derived CD133(+) and nestin(+) precursors, suggesting a regulatory effect on stem cells. In contrast, MDB cells undergo neuronal differentiation when treated with γ-secretase inhibitor, which prevents Notch activation. These results suggest that hypoxia, by maintaining Notch1 in its active form, preserves MDB stem cell viability and expansion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Antigens, CD / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Proliferation
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Glycoproteins / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunohistochemistry
  • Intermediate Filament Proteins / metabolism
  • Medulloblastoma / genetics
  • Medulloblastoma / metabolism*
  • Neoplastic Stem Cells / cytology*
  • Neoplastic Stem Cells / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Peptides / metabolism
  • Polymerase Chain Reaction
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Receptors, Notch / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Transcription Factor HES-1
  • Tumor Cells, Cultured


  • AC133 Antigen
  • Antigens, CD
  • Basic Helix-Loop-Helix Transcription Factors
  • Glycoproteins
  • Homeodomain Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intermediate Filament Proteins
  • NES protein, human
  • Nerve Tissue Proteins
  • Nestin
  • PROM1 protein, human
  • Peptides
  • Receptor, Notch1
  • Receptors, Notch
  • Transcription Factor HES-1
  • HES1 protein, human