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Poor vessel formation in embryos from knock-in mice expressing ALK5 with L45 loop mutation defective in Smad activation

Itoh, F. and Itoh, S. and Carvalho, R. and Adachi, T. and Ema, M. and Goumans, M.J. and Larsson, J. and Karlsson, S. and Takahashi, S. and Mummery, C.L. and Dijke ten, P. and Kato, M. (2009) Poor vessel formation in embryos from knock-in mice expressing ALK5 with L45 loop mutation defective in Smad activation. Laboratory investigation, 89, 800-10. ISSN 1530-0307.

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Official URL: http://dx.doi.org/10.1038/labinvest.2009.37

Abstract

Transforming growth factor (TGF)-beta regulates vascular development through two type I receptors: activin receptor-like kinase (ALK) 1 and ALK5, each of which activates a different downstream Smad pathway. The endothelial cell (EC)-specific ALK1 increases EC proliferation and migration, whereas the ubiquitously expressed ALK5 inhibits both of these processes. As ALK1 requires the kinase activity of ALK5 for optimal activation, the lack of ALK5 in ECs results in defective phosphorylation of both Smad pathways on TGF-beta stimulation. To understand why TGF-beta signaling through ALK1 and ALK5 has opposing effects on ECs and whether this takes place in vivo, we carefully compared the phenotype of ALK5 knock-in (ALK5(KI/KI)) mice, in which the aspartic acid residue 266 in the L45 loop of ALK5 was replaced by an alanine residue, with the phenotypes of ALK5 knock-out (ALK5(-/-)) and wild-type mice. The ALK5(KI/KI) mice showed angiogenic defects with embryonic lethality at E10.5-11.5. Although the phenotype of the ALK5(KI/KI) mice was quite similar to that of the ALK5(-/-) mice, the hierarchical structure of blood vessels formed in the ALK5(KI/KI) embryos was more developed than that in the ALK5(-/-) mutants. Thus, the L45 loop mutation in ALK5 partially rescued the earliest vascular defects in the ALK5(-/-) embryos. This study supports our earlier observation that vascular maturation in vivo requires both TGF-beta/ALK1/BMP-Smad and TGF-beta/ALK5/activin-Smad pathways for normal vascular development.

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:6988
Deposited On:25 Jan 2010 01:00
Last Modified:13 Oct 2010 12:51

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