Oxygen Levels Regulate the Development of Human Cortical Radial Glia Cells.
The oxygen (O2) concentration is a vital parameter for controlling the survival, proliferation, and differentiation of neural stem cells. A prenatal reduction of O2 levels (hypoxia) often leads to cognitive and behavioral defects, attributable to altered neural development. In this study, we analyzed the effects of O2 levels on human cortical progenitors, the radial glia cells (RGCs), during active neurogenesis, corresponding to the second trimester of gestation. Small changes in O2 levels profoundly affected RGC survival, proliferation, and differentiation. Physiological hypoxia (3% O2) promoted neurogenesis, whereas anoxia (<1% O2) and severe hypoxia (1% O2) arrested the differentiation of human RGCs, mainly by altering the generation of glutamatergic neurons. The in vitro activation of Wnt-β-catenin signaling rescued the proliferation and neuronal differentiation of RGCs subjected to anoxia. Pathologic hypoxia (≤1% O2) also exerted negative effects on gliogenesis, by decreasing the number of O4+ preoligodendrocytes and increasing the number of reactive astrocytes derived from cortical RGCs. O2-dependent alterations in glutamatergic neurogenesis and oligodendrogenesis can lead to significant changes in cortical circuitry formation. A better understanding of the cellular effects caused by changes in O2 levels during human cortical development is essential to elucidating the etiology of numerous neurodevelopmental disorders.
Department of Neuroscience, University of Connecticut Health, Farmington, CT 06030, USA.
J Alberto
JA
Ortega
Department of Neuroscience, University of Connecticut Health, Farmington, CT 06030, USA.|Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06030, USA.
Carissa L
CL
Sirois
Department of Neuroscience, University of Connecticut Health, Farmington, CT 06030, USA.
Fani
F
Memi
Department of Neuroscience, University of Connecticut Health, Farmington, CT 06030, USA.
Nicole
N
Glidden
Department of Neuroscience, University of Connecticut Health, Farmington, CT 06030, USA.
Nada
N
Zecevic
D000941:Antigens / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D063928:Ependymoglial Cells / Q000187:drug effects / Q000378:metabolism*; D000071438:Fatty Acid-Binding Protein 7 / Q000235:genetics / Q000378:metabolism; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005865:Gestational Age; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D000071438:Fatty Acid-Binding Protein 7; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D010100:Oxygen; D011509:Proteoglycans; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D000099216:Chondroitin Sulfate Proteoglycan 4; C107608:FABP7 protein, human; C497442:HIF1A protein, human
Wnt-β-catenin; cerebral cortex; cortical neurogenesis; hypoxia; neural stem cells