RRC ID 4281
Author Pocock R, Hobert O.
Title Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans.
Journal Nat. Neurosci.
Abstract Oxygen deprivation can cause severe defects in human brain development, yet the precise cellular and molecular consequences of varying oxygen levels on nervous system development are unknown. We found that hypoxia caused specific axon pathfinding and neuronal migration defects in C. elegans that result from the stabilization of the transcription factor HIF-1 (hypoxia-inducible factor 1) in neurons and muscle. Stabilization of HIF-1 through removal of the proteasomal HIF-1 degradatory pathway phenocopies the hypoxia-induced neuronal defects. Hypoxia-mediated defects in nervous system development depended on signaling through the insulin-like receptor DAF-2, which serves to control the level of reactive oxygen species that also affects axon pathfinding. Hypoxia exerted its effect on axon pathfinding, at least in part, through HIF-1-dependent regulation of the Eph receptor VAB-1. HIF-1-mediated upregulation of VAB-1 protected embryos from hypoxia-induced lethality, but increased VAB-1 levels elicited aberrant axon pathfinding. Similar genetic pathways may cause aberrant human brain development under hypoxic conditions.
Volume 11(8)
Pages 894-900
Published 2008-8
DOI 10.1038/nn.2152
PII nn.2152
PMID 18587389
MeSH Animals Animals, Genetically Modified Axons / drug effects Axons / physiology* Caenorhabditis elegans / embryology Caenorhabditis elegans / physiology* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism Cell Movement / drug effects Cell Movement / genetics Cell Movement / physiology* Embryo, Nonmammalian Growth Cones / drug effects Growth Cones / physiology Hypoxia* / genetics Hypoxia-Inducible Factor 1 / genetics Hypoxia-Inducible Factor 1 / physiology Muscles / metabolism Mutagenesis, Site-Directed Nervous System Malformations / etiology Neurons / drug effects Neurons / physiology* Neurons / ultrastructure Oxygen / metabolism* Oxygen / pharmacology Reactive Oxygen Species / metabolism Receptor Protein-Tyrosine Kinases / genetics Receptor Protein-Tyrosine Kinases / metabolism Receptor, Insulin / genetics Receptor, Insulin / metabolism Signal Transduction / genetics Signal Transduction / physiology Up-Regulation / genetics
IF 21.126
Times Cited 53
C.elegans tm776