Flt1 acts as a negative regulator of tip cell formation and branching morphogenesis in the zebrafish embryo

Krueger, Janna, Liu, Dong, Scholz, Katja, Zimmer, Anja, Shi, Yu, Klein, Christian, Siekmann, Arndt, Schulte-Merker, Stefan, Cudmore, Melissa, Ahmed, Asif and le Noble, Ferdinand (2011). Flt1 acts as a negative regulator of tip cell formation and branching morphogenesis in the zebrafish embryo. Development, 138 (10), pp. 2111-2120.

Abstract

Endothelial tip cells guide angiogenic sprouts by exploring the local environment for guidance cues such as vascular endothelial growth factor (VegfA). Here we present Flt1 (Vegf receptor 1) loss- and gain-of-function data in zebrafish showing that Flt1 regulates tip cell formation and arterial branching morphogenesis. Zebrafish embryos expressed soluble Flt1 (sFlt1) and membrane-bound Flt1 (mFlt1). In Tg(flt1(BAC):yfp) × Tg(kdrl:ras-cherry)(s916) embryos, flt1:yfp was expressed in tip, stalk and base cells of segmental artery sprouts and overlapped with kdrl:cherry expression in these domains. flt1 morphants showed increased tip cell numbers, enhanced angiogenic behavior and hyperbranching of segmental artery sprouts. The additional arterial branches developed into functional vessels carrying blood flow. In support of a functional role for the extracellular VEGF-binding domain of Flt1, overexpression of sflt1 or mflt1 rescued aberrant branching in flt1 morphants, and overexpression of sflt1 or mflt1 in controls resulted in short arterial sprouts with reduced numbers of filopodia. flt1 morphants showed reduced expression of Notch receptors and of the Notch downstream target efnb2a, and ectopic expression of flt4 in arteries, consistent with loss of Notch signaling. Conditional overexpression of the notch1a intracellular cleaved domain in flt1 morphants restored segmental artery patterning. The developing nervous system of the trunk contributed to the distribution of Flt1, and the loss of flt1 affected neurons. Thus, Flt1 acts in a Notch-dependent manner as a negative regulator of tip cell differentiation and branching. Flt1 distribution may be fine-tuned, involving interactions with the developing nervous system.

Publication DOI: https://doi.org/10.1242/dev.063933
Divisions: Life & Health Sciences
Life & Health Sciences > Biosciences
Life & Health Sciences > Cellular and Molecular Biomedicine
Aston Medical School
Uncontrolled Keywords: Flt1,VEGF,angiogenesis,Notch,tip cells,nerves,zebrafish,Developmental Biology,Molecular Biology
Full Text Link: https://www.ncb ... les/PMC3082310/
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
http://dev.biol ... ent/138/10/2111 (Publisher URL)
Published Date: 2011-05-15
Authors: Krueger, Janna
Liu, Dong
Scholz, Katja
Zimmer, Anja
Shi, Yu
Klein, Christian
Siekmann, Arndt
Schulte-Merker, Stefan
Cudmore, Melissa
Ahmed, Asif
le Noble, Ferdinand

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