Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling

Koji Taniguchi, Ri Ichiro Kohno, Toranoshin Ayada, Reiko Kato, Kenji Ichiyama, Toru Morisada, Yuichi Oike, Yoshikazu Yonemitsu, Yoshihiko Maehara, Akihiko Yoshimura

Research output: Contribution to journalArticle

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Abstract

Spred/Sprouty family proteins negatively regulate growth factor-induced ERK activation. Although the individual physiological roles of Spred-1 and Spred-2 have been investigated using gene-disrupted mice, the overlapping functions of Spred-1 and Spred-2 have not been clarified. Here, we demonstrate that the deletion of both Spred-1 and Spred-2 resulted in embryonic lethality at embryonic days 12.5 to 15.5 with marked subcutaneous hemorrhage, edema, and dilated lymphatic vessels filled with erythrocytes. This phenotype resembled that of Syk-/- and SLP-76-/- mice with defects in the separation of lymphatic vessels from blood vessels. The number of LYVE-1-positive lymphatic vessels and lymphatic endothelial cells increased markedly in Spred-1/2-deficient embryos compared with WT embryos, while the number of blood vessels was not different. Ex vivo colony assay revealed that Spred-1/2 suppressed lymphatic endothelial cell proliferation and/or differentiation. In cultured cells, the overexpression of Spred-1 or Spred-2 strongly suppressed vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3-mediated ERK activation, while Spred-1/2-deficient cells were extremely sensitive to VEGFR-3 signaling. These data suggest that Spreds play an important role in lymphatic vessel development by negatively regulating VEGF-C/VEGFR-3 signaling.

Original languageEnglish
Pages (from-to)4541-4550
Number of pages10
JournalMolecular and Cellular Biology
Volume27
Issue number12
DOIs
Publication statusPublished - 2007 Jun

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Vascular Endothelial Growth Factor Receptor-3
Lymphangiogenesis
Lymphatic Vessels
Vascular Endothelial Growth Factor C
Blood Vessels
Embryonic Structures
Endothelial Cells
Cell Differentiation
Cultured Cells
Edema
Intercellular Signaling Peptides and Proteins
Erythrocytes
Cell Proliferation
Hemorrhage
Phenotype
Genes
human FLT4 protein
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. / Taniguchi, Koji; Kohno, Ri Ichiro; Ayada, Toranoshin; Kato, Reiko; Ichiyama, Kenji; Morisada, Toru; Oike, Yuichi; Yonemitsu, Yoshikazu; Maehara, Yoshihiko; Yoshimura, Akihiko.

In: Molecular and Cellular Biology, Vol. 27, No. 12, 06.2007, p. 4541-4550.

Research output: Contribution to journalArticle

Taniguchi, Koji ; Kohno, Ri Ichiro ; Ayada, Toranoshin ; Kato, Reiko ; Ichiyama, Kenji ; Morisada, Toru ; Oike, Yuichi ; Yonemitsu, Yoshikazu ; Maehara, Yoshihiko ; Yoshimura, Akihiko. / Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. In: Molecular and Cellular Biology. 2007 ; Vol. 27, No. 12. pp. 4541-4550.
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