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Gridlock signalling pathway fashions the first embryonic artery

Nature volume 414, pages 216–220 (2001)Cite this article

Abstract

Arteries and veins are morphologically, functionally and molecularly very different, but how this distinction is established during vasculogenesis is unknown1,2. Here we show, by lineage tracking in zebrafish embryos, that angioblast precursors for the trunk artery and vein are spatially mixed in the lateral posterior mesoderm. Progeny of each angioblast, however, are restricted to one of the vessels. This arterial–venous decision is guided by gridlock (grl), an artery-restricted gene that is expressed in the lateral posterior mesoderm3. Graded reduction of grl expression, by mutation or morpholino antisense, progressively ablates regions of the artery, and expands contiguous regions of the vein, preceded by an increase in expression of the venous marker EphB4 receptor (ephb4)2 and diminution of expression of the arterial marker ephrin-B2 (efnb2)2. grl is downstream of notch4, and interference with notch signalling, by blocking Su(H)4, similarly reduces the artery and increases the vein. Thus, a notch–grl pathway controls assembly of the first embryonic artery, apparently by adjudicating an arterial versus venous cell fate decision.

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Figure 1: Tracking the lineage of pre-arterial and pre-venous angioblasts from the lateral posterior mesoderm to the trunk vessels.
Figure 2: Reduction in Grl produces graded loss of regions of the aorta and expansion of veins.
Figure 3: Injection of grl into wild-type embryos reduces the vein.
Figure 4: Expression of grl is increased by injection of activated notch1 and blocked by the dominant negative inhibitor of Su(H).
Figure 5: Reduction of Grl causes an increase of ephb4 expression and decrease of ephb2 expression.

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Acknowledgements

We thank members of the Fishman laboratory for advice during these experiments, especially J.-N. Chen for help with the preliminary work on lineage analysis and C. Simpson for histological analyses. We thank S. Artavanis-Tsakonas and M. Rand for human Notch1-ICD construct; C. Kintner for Xenopus notch-ICD and Su(H)-Dbm constructs; and J. Chen for zebrafish ephrin-B2 and EphB4 probes. J.P.L. was supported by the Sarnoff Foundation. This work is supported by grants from the National Institutes of Health and a sponsored research agreement with Genentech to M.C.F.

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Author notes

  1. Tao P. Zhong

    Present address: Department of Medicine and Cell Biology, Vanderbilt Medical School, Nashville, Tennessee, 37232, USA

  2. Sarah Childs

    Present address: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, T2N 4N1, Canada

  3. Mark C. Fishman: Correspondence and requests for materials should be addressed to M.C.F.

Authors and Affiliations

  1. Massachusetts General Hospital; Department of Medicine, Cardiovascular Research Center, Harvard Medical School, 149 13th Street, Charlestown, 02129, Massachusetts, USA

    Tao P. Zhong, Sarah Childs, James P. Leu & Mark C. Fishman

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Correspondence to Mark C. Fishman.

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Zhong, T., Childs, S., Leu, J. et al. Gridlock signalling pathway fashions the first embryonic artery. Nature 414, 216–220 (2001). https://doi.org/10.1038/35102599

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