title: Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis.
abstract: Blood vessels are part of the stem cell niche in the developing cerebral cortex, but their in vivo role in controlling the expansion and differentiation of neural stem cells (NSCs) in development has not been studied. Here, we report that relief of hypoxia in the developing cerebral cortex by ingrowth of blood vessels temporo-spatially coincided with NSC differentiation. Selective perturbation of brain angiogenesis in vessel-specific Gpr124 null embryos, which prevented the relief from hypoxia, increased NSC expansion at the expense of differentiation. Conversely, exposure to increased oxygen levels rescued NSC differentiation in Gpr124 null embryos and increased it further in WT embryos, suggesting that niche blood vessels regulate NSC differentiation at least in part by providing oxygen. Consistent herewith, hypoxia-inducible factor (HIF)-1α levels controlled the switch of NSC expansion to differentiation. Finally, we provide evidence that high glycolytic activity of NSCs is required to prevent their precocious differentiation in vivo Thus, blood vessel function is required for efficient NSC differentiation in the developing cerebral cortex by providing oxygen and possibly regulating NSC metabolism.
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven Leuven, Belgium.
authors: Christian
authors: C
authors: Lange
authors: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors: Miguel
authors: M
authors: Turrero Garcia
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven Leuven, Belgium.
authors: Ilaria
authors: I
authors: Decimo
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven Leuven, Belgium.
authors: Francesco
authors: F
authors: Bifari
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven Leuven, Belgium.
authors: Guy
authors: G
authors: Eelen
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven Leuven, Belgium.
authors: Annelies
authors: A
authors: Quaegebeur
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven Leuven, Belgium.
authors: Ruben
authors: R
authors: Boon
authors: Laboratory of Translational Genetics, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Translational Genetics, Department of Oncology, KU Leuven Leuven, Belgium.
authors: Hui
authors: H
authors: Zhao
authors: Laboratory of Translational Genetics, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Translational Genetics, Department of Oncology, KU Leuven Leuven, Belgium.
authors: Bram
authors: B
authors: Boeckx
authors: Department of Medicine, Hematology Division Stanford University, Stanford, CA, USA.
authors: Junlei
authors: J
authors: Chang
authors: Department of Medicine, Hematology Division Stanford University, Stanford, CA, USA.
authors: Christine
authors: C
authors: Wu
authors: Angiogenesis and Cardiovascular Pathology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany Department of Cell and Developmental Biology, KIT, Karlsruhe, Germany.
authors: Ferdinand
authors: F
authors: Le Noble
authors: Laboratory of Translational Genetics, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Translational Genetics, Department of Oncology, KU Leuven Leuven, Belgium.
authors: Diether
authors: D
authors: Lambrechts
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven Leuven, Belgium.
authors: Mieke
authors: M
authors: Dewerchin
authors: Department of Medicine, Hematology Division Stanford University, Stanford, CA, USA.
authors: Calvin J
authors: CJ
authors: Kuo
authors: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors: Wieland B
authors: WB
authors: Huttner
authors: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven Leuven, Belgium peter.carmeliet@vib-kuleuven.be.
authors: Peter
authors: P
authors: Carmeliet
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000196:embryology*; D006019:Glycolysis; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D051379:Mice; D018919:Neovascularization, Physiologic; D058953:Neural Stem Cells / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen
keywords: hypoxia; neural stem cell; neurogenesis; stem cell metabolism; vascular niche