Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans

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.

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Figure 1: Hypoxia causes cell-specific defects in the C. elegans nervous system.
Figure 2: The conserved HIF-1 regulatory pathway mediates the effects of hypoxia on nervous system development.
Figure 3: Reduction of daf-2 signaling suppresses hypoxia-induced PVQL/R axon-pathfinding defects, probably through detoxification of ROS.
Figure 4: vab-1 is upregulated by hypoxia and causes PVQL/R axon-pathfinding defects.
Figure 5: vab-1 acts non-autonomously to cause axon-pathfinding defects.

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Acknowledgements

We thank Q. Chen for expert technical assistance in generating transgenic strains, A. Clarke for technical help, the Caenorhabditis Genetics Center and J.A. Powell-Coffman for providing strains, M. Krause for the unc-120 promoter, the C. elegans knockout consortia lead by R. Barstead, D. Moerman and S. Mitani for gk, ok and tm alleles, respectively, T. Boulin for the pF25B3.3::vab-1 construct and communicating results on lin-18, and I. Greenwald and members of the Hobert lab for comments on the manuscript. This work was funded in part by the Muscle Dystrophy Association (O.H.). O.H. is an investigator of the Howard Hughes Medical Institute.

Author information

R.P. designed and conducted the experiments and wrote the manuscript. O.H. supervised the project, gave suggestions and helped write the manuscript.

Correspondence to Roger Pocock or Oliver Hobert.

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Supplementary Figures 1 and 2, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 475 kb)

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Pocock, R., Hobert, O. Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans. Nat Neurosci 11, 894–900 (2008) doi:10.1038/nn.2152

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