The LIM-homeodomain transcription factor Islet2a promotes angioblast migration

Abstract

Angioblasts of the developing vascular system require many signaling inputs to initiate their migration, proliferation and differentiation into endothelial cells. What is less studied is which intrinsic cell factors interpret these extrinsic signals. Here, we show the Lim homeodomain transcription factor islet2a (isl2a) is expressed in the lateral posterior mesoderm prior to angioblast migration. isl2a deficient angioblasts show disorganized migration to the midline to form axial vessels and fail to spread around the tailbud of the embryo. Isl2a morphants have fewer vein cells and decreased vein marker expression. We demonstrate that isl2a is required cell autonomously in angioblasts to promote their incorporation into the vein, and is permissive for vein identity. Knockout of isl2a results in decreased migration and proliferation of angioblasts during intersegmental artery growth. Since Notch signaling controls both artery-vein identity and tip-stalk cell formation, we explored the interaction of isl2a and Notch. We find that isl2a expression is negatively regulated by Notch activity, and that isl2a positively regulates flt4, a VEGF-C receptor repressed by Notch during angiogenesis. Thus Isl2a may act as an intermediate between Notch signaling and genetic programs controlling angioblast number and migration, placing it as a novel transcriptional regulator of early angiogenesis.

Fine-tune regulation of carboxypeptidase N1 controls vascular patterning during zebrafish development

“…Our previous studies found the vascular functions of Isl2 and Nr2f1b are mediated by Notch signaling 18, 19 . In this study, we demonstrated that cpn1 functions in the vasculature are mediated by VEGF and Notch signals.…”

“…In our previous study, we identified the function of the transcription factors Isl2 and Nr2f1b in the vasculature mediated by Notch signals 18, 19 . Our Isl2/Nr2f1b transcriptomal analysis suggested that cpn1 acts a potential function in the vasculature.…”

“…Current evidence suggests that VEGFC/VEGFR3 (flt4) signaling is essential for vein identity and ISV tip cell identity mediated by VEGFA/VEGFR2 signal and inactivation of Notch signal 13, 14 , and BMP signaling is involved in CVP formation 15–17 . Our recent studies found that transcription factors Isl2 and Nr2f1b are crucial novel determinants of vein identity, ISV growth, and CVP patterning 18, 19 . Our Isl2/Nr2f1b transcriptomal analysis showed cpn1 , that encodes the carboxypeptidase N subunit 1, is highly responsive and we hypothesized that cpn1 plays a potential role in the vascular development.…”

Coral-Derived Natural Marine Compound GB9 Impairs Vascular Development in Zebrafish

“…Antisense riboprobes were synthesized using T7 polymerase with a DIG RNA labeling kit (Roche) according to the manufacturer’s instructions. The ephrinb2 , mrc1 , flk , and stabilin probes have been described [ 22 , 49 , 50 ]. The whole-mount in situ hybridization protocol was based on Thisse et al [ 51 ].…”

“…In addition, the cellular and molecular mechanisms underlying vascular development have been shown to be conserved in vertebrates. The zebrafish model has been successfully used to reveal molecular mechanisms of blood vessel formation, such as angioblast specification and differentiation, endothelial cell proliferation and migration, vessel formation, patterning, and morphogenesis [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. In addition, the zebrafish model has been widely used to examine the effects of chemicals, drugs, and environmental hormones in vascular development [ 24 , 25 ].…”