Nature 445, 781-784 (15 February 2007) | doi:10.1038/nature05577; Received 16 October 2006; Accepted 8 January 2007; Published online 28 January 2007

Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries

Arndt F. Siekmann1 & Nathan D. Lawson1

  1. Program in Gene Function and Expression, University of Massachusetts Medical School, Lazare Research Building, 364 Plantation Street, Worcester, Massachusetts 01605, USA

Correspondence to: Nathan D. Lawson1 Correspondence and requests for materials should be addressed to N.D.L (Email: nathan.lawson@umassmed.edu).

Recent evidence indicates that growing blood-vessel sprouts consist of endothelial cells with distinct cell fates and behaviours1, 2; however, it is not clear what signals determine these sprout cell characteristics. Here we show that Notch signalling is necessary to restrict angiogenic cell behaviour to tip cells in developing segmental arteries in the zebrafish embryo. In the absence of the Notch signalling component Rbpsuh (recombining binding protein suppressor of hairless) we observed excessive sprouting of segmental arteries, whereas Notch activation suppresses angiogenesis. Through mosaic analysis we find that cells lacking Rbpsuh preferentially localize to the terminal position in developing sprouts. In contrast, cells in which Notch signalling has been activated are excluded from the tip-cell position. In vivo time-lapse analysis reveals that endothelial tip cells undergo a stereotypical pattern of proliferation and migration during sprouting. In the absence of Notch, nearly all sprouting endothelial cells exhibit tip-cell behaviour, leading to excessive numbers of cells within segmental arteries. Furthermore, we find that flt4 (fms-related tyrosine kinase 4, also called vegfr3) is expressed in segmental artery tip cells and becomes ectopically expressed throughout the sprout in the absence of Notch. Loss of flt4 can partially restore normal endothelial cell number in Rbpsuh-deficient segmental arteries. Finally, loss of the Notch ligand dll4 (delta-like 4) also leads to an increased number of endothelial cells within segmental arteries. Together, these studies indicate that proper specification of cell identity, position and behaviour in a developing blood-vessel sprout is required for normal angiogenesis, and implicate the Notch signalling pathway in this process.


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