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First published online 4 March 2009
doi: 10.1242/dev.034199

Development 136, 1263-1272 (2009)
Published by The Company of Biologists 2009
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The forming limb skeleton serves as a signaling center for limb vasculature patterning via regulation of Vegf

Idit Eshkar-Oren1, Sergey V. Viukov1, Sharbel Salameh1, Sharon Krief1, Chun-do Oh2, Haruhiko Akiyama3, Hans-Peter Gerber4, Napoleone Ferrara4 and Elazar Zelzer1,*

1 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
2 Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
3 Department of Orthopaedics, Kyoto University, Kyoto 606-8507, Japan.
4 Genentech, 1 DNA Way, S. San Francisco, CA 94080, USA.

* Author for correspondence (e-mail: eli.zelzer{at}weizmann.ac.il)

Accepted 16 February 2009

Limb development constitutes a central model for the study of tissue and organ patterning; yet, the mechanisms that regulate the patterning of limb vasculature have been left understudied. Vascular patterning in the forming limb is tightly regulated in order to ensure sufficient gas exchange and nutrient supply to the developing organ. Once skeletogenesis is initiated, limb vasculature undergoes two seemingly opposing processes: vessel regression from regions that undergo mesenchymal condensation; and vessel morphogenesis. During the latter, vessels that surround the condensations undergo an extensive rearrangement, forming a stereotypical enriched network that is segregated from the skeleton. In this study, we provide evidence for the centrality of the condensing mesenchyme of the forming skeleton in regulating limb vascular patterning. Both Vegf loss- and gain-of-function experiments in limb bud mesenchyme firmly established VEGF as the signal by which the condensing mesenchyme regulates the vasculature. Normal vasculature observed in limbs where VEGF receptors Flt1, Flk1, Nrp1 and Nrp2 were blocked in limb bud mesenchyme suggested that VEGF, which is secreted by the condensing mesenchyme, regulates limb vasculature via a direct long-range mechanism. Finally, we provide evidence for the involvement of SOX9 in the regulation of Vegf expression in the condensing mesenchyme. This study establishes Vegf expression in the condensing mesenchyme as the mechanism by which the skeleton patterns limb vasculature.

Key words: Skeleton, Skeletogenesis, Anti-angiogenic, Vascular patterning, Limb development, SOX9, VEGF, PRX1-Cre, SOX9-Cre, Mouse


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© The Company of Biologists Ltd 2009