Selective Role of a Distinct Tyrosine Residue on Tie2 in Heart Development and Early Hematopoiesis

Abstract

The development of the cardiovascular system and the development of the early hematopoietic systems are closely related, and both require signaling through the Tie2 receptor tyrosine kinase. Although endothelial cells and hematopoietic cells as well as their precursors share common gene expression patterns during development, it remains completely unknown how Tie2 signaling coordinately regulates cardiovascular development and early hematopoiesis in vivo. We show here that mice with a targeted mutation in tyrosine residue 1100 in the carboxyl-terminal tail of Tie2 display defective cardiac development and impaired hematopoietic and endothelial cell development in the paraaortic splanchnopleural mesoderm similar to that seen in Tie2-null mutant mice. Surprisingly, however, unlike Tie2-null mutant mice, mice deficient in signaling through this tyrosine residue show a normal association of perivascular cells with nascent blood vessels. These studies are the first to demonstrate the physiological importance of a single tyrosine residue in Tie2, and they suggest that multiple tyrosine residues in the receptor may coordinate cardiovascular development and early hematopoietic development.

ACKNOWLEDGMENTS

We thank S. Tondat and S. MacMaster for ES cell aggregations; M. Peralta for histological sections; D. P. Holmyard, M. Hirashima, and K. Chawengsaksophak for assistance with electron microscopic, fluorescence-activated cell sorting, and fluorescence immunostaining analyses, respectively; N. Takakura and T. Yokomizo for advice on P-Sp culturing and whole-mount immunostaining of c-Kit⁺ clusters, respectively; W. R. Hardy and T. Pawson for providing ShcA mutant mice; Y. Yamanaka for critical reading of the manuscript; and all members of the Bernstein Laboratory for helpful discussions.

This work was supported in part by the National Cancer Institute of Canada (A.B.), a Canadian Institutes of Health research fellowship and a Uehara Memorial Foundation fellowship (K.T.), a National Cancer Institute of Canada/Terry Fox Run research fellowship (N.J.), and a scientist award from the Canadian Institutes of Health Research (D.J.D.).

The authors declare that they have no competing financial interests.