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Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain

Nature Neuroscience volume 11, pages 429–439 (2008)Cite this article

Abstract

Prevailing notions of cerebral vascularization imply that blood vessels sprout passively into the brain parenchyma from pial vascular plexuses to meet metabolic needs of growing neuronal populations. Endothelial cells, building blocks of blood vessels, are thought to be homogeneous in the brain with respect to their origins, gene expression patterns and developmental mechanisms. These current notions that cerebral angiogenesis is regulated by local environmental signals contrast with current models of cell-autonomous regulation of neuronal development. Here we demonstrate that telencephalic angiogenesis in mice progresses in an orderly, ventral-to-dorsal gradient regulated by compartment-specific homeobox transcription factors. Our data offer new perspectives on intrinsic regulation of angiogenesis in the embryonic telencephalon, call for a revision of the current models of telencephalic angiogenesis and support novel roles for endothelial cells in brain development.

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Figure 1: Angiogenesis gradients in the embryonic telencephalon.
Figure 2: Dorsal periventricular vessels originate from the ventral telencephalon.
Figure 3: Ventral-to-dorsal migration of endothelial cells.
Figure 4: Endothelial cells express homeobox transcription factors.
Figure 5: Nkx2.1 and Dlx1/2 regulate telencephalic angiogenesis.
Figure 6: Ventral homeobox genes regulate endothelial cell migration and proliferation.
Figure 7: Telencephalic angiogenesis in SeyDey mutant mice.
Figure 8: Cell autonomous regulation of endothelial cell migration by Nkx2.1 and Pax6.

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Acknowledgements

We thank S. Anderson (Weill-Cornell Medical College) for sharing with us the Nkx2.1+/− line. We gratefully acknowledge technical assistance by I. Bagayev (confocal microscope), L. Zagachin (real-time PCR) and M. Waring (FACS). This work was supported by RO1NS43246, RO1DA020796 and P30NS045776 to P.G.B.

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Authors and Affiliations

  1. Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Anju Vasudevan & Pradeep G Bhide

  2. Department of Psychiatry, Nina Ireland Laboratory of Developmental Neurobiology, University of California at San Francisco, San Francisco, 94158, California, USA

    Jason E Long & John L R Rubenstein

  3. E.K. Shriver Center for Mental Retardation, University of Massachusetts Medical School, Waltham, 02452, Massachusetts, USA

    James E Crandall

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  1. Anju Vasudevan
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Contributions

A.V. and P.G.B. designed the experiments and wrote the manuscript. A.V. conducted the experiments. J.E.L. and J.L.R.R. provided Dlx1/2 mutant and wild-type embryos; J.E.C. supplied reeler mutant and wild-type embryos and all three commented on earlier versions of the manuscript.

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Correspondence to Anju Vasudevan or Pradeep G Bhide.

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Vasudevan, A., Long, J., Crandall, J. et al. Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain. Nat Neurosci 11, 429–439 (2008). https://doi.org/10.1038/nn2074

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