Hypoxia Requires Notch Signaling to Maintain the Undifferentiated Cell State

• Published in: Developmental cell 2005-11, Vol.9 (5), p.617-628
• Main Authors: Gustafsson, Maria V., Zheng, Xiaowei, Pereira, Teresa, Gradin, Katarina, Jin, Shaobo, Lundkvist, Johan, Ruas, Jorge L., Poellinger, Lorenz, Lendahl, Urban, Bondesson, Maria
• Format: Article
• Language: English
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - drug effects; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Carbamates - pharmacology; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell differentiation, maturation, development, hematopoiesis; Cell Line; Cell Line, Tumor; Cell physiology; Dipeptides - pharmacology; Fundamental and applied biological sciences. Psychology; Homeodomain Proteins - drug effects; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Medicin och hälsovetenskap; Mice; Molecular and cellular biology; Myoblasts - cytology; Myoblasts - drug effects; Myoblasts - metabolism; Receptor, Notch1 - metabolism; Receptors, Notch - drug effects; Receptors, Notch - genetics; Receptors, Notch - physiology; Repressor Proteins - drug effects; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Transcription Factor HES-1
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2005.09.010

In addition to controlling a switch to glycolytic metabolism and induction of erythropoiesis and angiogenesis, hypoxia promotes the undifferentiated cell state in various stem and precursor cell populations. Here, we show that the latter process requires Notch signaling. Hypoxia blocks neuronal and myogenic differentiation in a Notch-dependent manner. Hypoxia activates Notch-responsive promoters and increases expression of Notch direct downstream genes. The Notch intracellular domain interacts with HIF-1α, a global regulator of oxygen homeostasis, and HIF-1α is recruited to Notch-responsive promoters upon Notch activation under hypoxic conditions. Taken together, these data provide molecular insights into how reduced oxygen levels control the cellular differentiation status and demonstrate a role for Notch in this process.