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RESEARCH COMMUNICATION
1 CIISA, Faculdade de Medicina Veterinária, 1300-0-477 Lisboa, Portugal; 2 Instituto de Medicina Molecular, Faculdade de Medicina, 1649-9-028 Lisboa, Portugal; 3 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G1X5; 4 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8
Involvement of the Notch signaling pathway in vascular development has been demonstrated by both gain- and loss-of-function mutations in humans, mice, and zebrafish. In zebrafish, Notch signaling is required for arterial identity by suppressing the venous fate in developing artery cells. In mice, the Notch4 receptor and the Delta-like 4 (Dll4) ligand are specifically expressed in arterial endothelial cells, suggesting a similar role. Here we show that the Dll4 ligand alone is required in a dosage-sensitive manner for normal arterial patterning in development. This implicates Dll4 as the specific mammalian endothelial ligand for autocrine endothelial Notch signaling, and suggests that Dll4 may be a suitable target for intervention in arterial angiogenesis.
[Keywords: Angiogenesis; Dll4; Notch; haploinsufficiency; dosage sensitivity; arteriogenesis]
Received July 12, 2004; revised version accepted August 19, 2004.
5 These authors contributed equally to this work.
6 Present address: Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-0-8582, Japan.
7 Corresponding author. E-MAIL: rossant{at}mshri.on.ca; FAX (416) 586-8588.
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