Journal
CELL REPORTS
Volume 11, Issue 10, Pages 1577-1590Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.05.018
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Funding
- Wellcome Trust [095623/Z/11/Z]
- British Heart Foundation [PG/10/86/28622]
- Medical Research Council [MR/L003775/1]
- British Heart Foundation [FS/13/35/30148, FS/13/60/30457, PG/11/61/29008, RG/11/11/29050, RG/06/003/21131, PG/10/86/28622] Funding Source: researchfish
- Medical Research Council [MR/L003775/1] Funding Source: researchfish
- MRC [MR/L003775/1] Funding Source: UKRI
- Wellcome Trust [095623/Z/11/Z] Funding Source: Wellcome Trust
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Sprouting blood vessels are led by filopodia-studded endothelial tip cells that respond to angiogenic signals. Mosaic lineage tracing previously revealed that NRP1 is essential for tip cell function, although its mechanistic role in tip cells remains poorly defined. Here, we show that NRP1 is dispensable for genetic tip cell identity. Instead, we find that NRP1 is essential to form the filopodial bursts that distinguish tip cells morphologically from neighboring stalk cells, because it enables the extracellular matrix (ECM)-induced activation of CDC42, a key regulator of filopodia formation. Accordingly, NRP1 knockdown and pharmacological CDC42 inhibition similarly impaired filopodia formation in vitro and in developing zebrafish in vivo. During mouse retinal angiogenesis, CDC42 inhibition impaired tip cell and vascular network formation, causing defects that resembled those due to loss of ECM-induced, but not VEGF-induced, NRP1 signaling. We conclude that NRP1 enables ECM-induced filopodia formation for tip cell function during sprouting angiogenesis.
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