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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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.
References
Inoue, A. et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc. Natl Acad. Sci. USA 86, 2863–2867 (1989)
Arai, H., Hori, S., Aramori, I., Ohkubo, H. & Nakanishi, S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348, 730–732 (1990)
Sakurai, T. et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 348, 732–735 (1990)
Schotzinger, R. J. & Landis, S. C. Cholinergic phenotype developed by noradrenergic sympathetic neurons after innervation of a novel cholinergic target in vivo. Nature 335, 637–639 (1988)
Hiruma, T., Nakajima, Y. & Nakamura, H. Development of pharyngeal arch arteries in early mouse embryo. J. Anat. 201, 15–29 (2002)
Jiang, X., Rowitch, D. H., Soriano, P., McMahon, A. P. & Sucov, H. M. Fate of the mammalian cardiac neural crest. Development 127, 1607–1616 (2000)
Choudhary, B. et al. Cardiovascular malformations with normal smooth muscle differentiation in neural crest-specific type II TGFβ receptor (Tgfbr2) mutant mice. Dev. Biol. 289, 420–429 (2006)
Xu, D. et al. ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1. Cell 78, 473–485 (1994)
Yanagisawa, H. et al. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 125, 825–836 (1998)
Yanagisawa, H. et al. Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development. J. Clin. Invest. 105, 1373–1382 (2000)
Guthrie, S. & Lumsden, A. Collagen gel coculture of neural tissue. Neuroprotocols 4, 116–120 (1994)
Ihara, M. et al. In vitro biological profile of a highly potent novel endothelin (ET) antagonist BQ-123 selective for the ETA receptor. J. Cardiovasc. Pharmacol. 20 (suppl. 12). S11–S14 (1992)
Ishikawa, K. et al. Biochemical and pharmacological profile of a potent and selective endothelin B-receptor antagonist, BQ-788. Proc. Natl Acad. Sci. USA 91, 4892–4896 (1994)
Gariepy, C. E., Cass, D. T. & Yanagisawa, M. Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color. Proc. Natl Acad. Sci. USA 93, 867–872 (1996)
Clouthier, D. E. et al. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125, 813–824 (1998)
Baynash, A. G. et al. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79, 1277–1285 (1994)
Firth, J. D. & Ratcliffe, P. J. Organ distribution of the three rat endothelin messenger RNAs and the effects of ischemia on renal gene expression. J. Clin. Invest. 90, 1023–1031 (1992)
Danielian, P. S., Muccino, D., Rowitch, D. H., Michael, S. K. & McMahon, A. P. Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr. Biol. 8, 1323–1326 (1998)
Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nature Genet. 21, 70–71 (1999)
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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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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DOI: https://doi.org/10.1038/nature06859
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