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, Tohru Morisada, Yuichi Oike, Yoshikazu Yonemitsu, Yoshihiko Maehara, Akihiko Yoshimura

Research output: Contribution to journalArticle

93 Citations (Scopus)

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 - Jun 1 2007

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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

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Taniguchi, K., Kohno, R. I., Ayada, T., Kato, R., Ichiyama, K., Morisada, T., ... Yoshimura, A. (2007). Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. Molecular and cellular biology, 27(12), 4541-4550. https://doi.org/10.1128/MCB.01600-06

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, Tohru; Oike, Yuichi; Yonemitsu, Yoshikazu; Maehara, Yoshihiko; Yoshimura, Akihiko.

In: Molecular and cellular biology, Vol. 27, No. 12, 01.06.2007, p. 4541-4550.

Research output: Contribution to journalArticle

Taniguchi, K, Kohno, RI, Ayada, T, Kato, R, Ichiyama, K, Morisada, T, Oike, Y, Yonemitsu, Y, Maehara, Y & Yoshimura, A 2007, 'Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling', Molecular and cellular biology, vol. 27, no. 12, pp. 4541-4550. https://doi.org/10.1128/MCB.01600-06
Taniguchi, Koji ; Kohno, Ri Ichiro ; Ayada, Toranoshin ; Kato, Reiko ; Ichiyama, Kenji ; Morisada, Tohru ; 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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