title: The forming limb skeleton serves as a signaling center for limb vasculature patterning via regulation of Vegf.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Idit
authors.initials: I
authors.lastname: Eshkar-Oren
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Viukov
authors.forename: Sharbel
authors.initials: S
authors.lastname: Salameh
authors.forename: Sharon
authors.initials: S
authors.lastname: Krief
authors.forename: Chun-do
authors.initials: CD
authors.lastname: Oh
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Gerber
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Elazar
authors.initials: E
authors.lastname: Zelzer
mesh_terms: D000818:Animals; D019521:Body Patterning; D001842:Bone and Bones / Q000098:blood supply* / Q000196:embryology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018878:Limb Buds / Q000098:blood supply* / Q000196:embryology / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D042461:Vascular Endothelial Growth Factor A