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Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons

Abstract

During development, sympathetic neurons extend axons along a myriad of distinct trajectories, often consisting of arteries, to innervate one of a large variety of distinct final target tissues. Whether or not subsets of neurons within complex sympathetic ganglia are predetermined to innervate select end-organs is unknown. Here we demonstrate in mouse embryos that the endothelin family member Edn3 (ref. 1), acting through the endothelin receptor EdnrA (refs 2, 3), directs extension of axons of a subset of sympathetic neurons from the superior cervical ganglion to a preferred intermediate target, the external carotid artery, which serves as the gateway to select targets, including the salivary glands. These findings establish a previously unknown mechanism of axonal pathfinding involving vascular-derived endothelins, and have broad implications for endothelins as general mediators of axonal growth and guidance in the developing nervous system. Moreover, they suggest a model in which newborn sympathetic neurons distinguish and choose between distinct vascular trajectories to innervate their appropriate end organs.

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Figure 1: Development of vascular and sympathetic systems.
Figure 2: Expression of endothelin signalling components.
Figure 3: Endothelins promote SCG neurite outgrowth in vitro.
Figure 4: Edn3 and its receptor EdnrA are essential for SCG axonal projections along the external but not internal carotid arteries in mouse embryos.

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Gene Expression Omnibus

Data deposits

Microarray data referred to in this study have been deposited in the Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo) under the accession number GSE10360.

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Acknowledgements

We thank C. Deppmann, A. Kolodkin, J. Merte, S. Sockanathan and L. Schramm for comments on this manuscript, and S. Dixon and N. Murakami for technical support. This research was supported by grants from the National Institutes of Health (to H.M.S., C.E.G., M.Y. and D.D.G.). M.Y. and D.D.G. are investigators of the Howard Hughes Medical Institute.

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Correspondence to David D. Ginty.

Supplementary information

Supplementary information

The file contains Supplementary Methods and Supplementary Figures 1-5 with Legends. A revised version of Supplementary Fig. 4 was uploaded on 19 June 2008. The original Supplementary Fig. 4 reported findings from Ednrb mutant rat embryos that harboured an additional, unintended transgenic allele. This mutant rat exhibited normal axonal projections from the SCG. Supplementary Fig. 4 now contains results obtained from a control and a non-transgenic rat Ednrb mutant embryo, which has the correct genotype (that is, lacking the transgene). The new panels show findings that are indistinguishable from those of the previous panels, leading to the same conclusion as described in the manuscript. (PDF 3008 kb)

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Makita, T., Sucov, H., Gariepy, C. et al. Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons. Nature 452, 759–763 (2008). https://doi.org/10.1038/nature06859

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