Biology subjects

Coxam, B.

Publications and source records attributed to Coxam, B..

5 recordsLinked to original sources

bioRxiv2021

Pkd1 and Wnt5a genetically interact to control lymphatic vascular morphogenesis in mice

Lymphatic vascular development is regulated by well-characterised signalling and transcriptional pathways. These pathways regulate lymphatic endothelial cell (LEC) migration, motility, polarity and and morphogenesis. Canonical and non-canonical WNT signalling pathways are known to control LEC polarity and development of lymphatic vessels and valves. PKD1, encoding Polycystin-1, is the most commonly mutated gene in polycystic kidney disease but has also been shown to be essential in lymphatic vascular morphogenesis. The mechanism by which Pkd1 acts during lymphangiogenesis remains unclear. Here we find that loss of non-canonical WNT signalling components Wnt5a and Ryk phenocopy lymphatic defects seen in Pkd1 knockout mice. To investigate genetic interaction, we generated Pkd1/Wnt5a double knockout mice. Loss of Wnt5a suppressed phenotypes seen in the lymphatic vasculature of Pkd1-/- mice and Pkd1 deletion suppressed phenotypes observed in Wnt5a-/- mice. Thus, we report mutually suppressive roles for Pkd1 and Wnt5a, with developing lymphatic networks restored to a more wild-type state in double mutant mice. This genetic interaction between Pkd1 and the non-canonical WNT signalling pathway ultimately controls LEC polarity and the morphogenesis of developing vessel networks. Our work suggests that Pkd1 acts at least in part by regulating non-canonical WNT signalling during the formation of lymphatic vascular networks.

developmental biology↗

bioRxiv2021

Svep1 stabilizes developmental vascular anastomosis in reduced flow conditions.

We report the discovery that flow and Svep1 are modulator of vessel anastomosis during developmental angiogenesis in zebrafish embryos. We show that loss of Svep1 and blood flow reduction both contribute to defective anastomosis of intersegmental vessels. We show that this defect in primary angiogenic sprouts is associated with an expansion of Apelin-positive tip cells and with reduced formation and lumenisation of the dorsal longitudinal anastomotic vessel. Mechanistically, our results suggest that flow and Svep1 act synergistically to modulate vascular network formation in the zebrafish trunk.

developmental biology↗

bioRxiv2020

Wasp controls oriented migration of endothelial cells to achieve functional vascular patterning

Endothelial cell migration and proliferation are essential for the establishment of a hierarchical organization of blood vessels and optimal distribution of blood. However, how these cellular processes are coordinated remains unknown. Here, using the zebrafish trunk vasculature we show that in future veins endothelial cells proliferate more than in future arteries and migrate preferentially towards neighboring arteries. In future arteries endothelial cells show a biphasic migration profile. During sprouting cells move away from the dorsal aorta, during remodelling cells stop or move towards the feeding aorta. The final morphology of blood vessels is thus established by local proliferation and oriented cell migration to and from neighboring vessels. Additionally, we identify WASp to be essential for this differential migration. Loss of WASp leads to irregular distribution of endothelial cells, substantially enlarged veins and persistent arteriovenous shunting. Mechanistically, we report that WASp drives the assembly of junctional associated actin filaments and is required for junctional expression of PECAM-1. Together, our data identify that functional vascular patterning in the zebrafish trunk utilizes differential cell movement regulated by junctional actin, and that interruption of differential migration may represent a pathomechanism in vascular malformations.

developmental biology↗

bioRxiv2020

Vasohibin-1 mediated tubulin detyrosination selectively regulates secondary sprouting and lymphangiogenesis in the zebrafish trunk

Previous studies have shown that Vasohibin-1 (Vash-1) is stimulated by VEGFs in endothelial cells and that its overexpression interferes with angiogenesis in vivo. Recently, Vasohibin-1 was found to mediate tubulin detyrosination, a post-translational modification that is implicated in many cell functions, such as cell division. Here we used the zebrafish embryo to investigate the cellular and subcellular mechanisms of Vash-1 on endothelial microtubules during formation of the trunk vasculature. We show that microtubules within venous-derived secondary sprouts are strongly and selectively detyrosinated in comparison with other endothelial cells, and that this difference is lost upon vash-1 knockdown. Vasohibin-1 depletion in zebrafish specifically affected secondary sprouting from the posterior cardinal vein, increasing both the number of sprouts and endothelial cell divisions. We show that altering secondary sprout numbers and structure upon vash-1 depletion leads to a failure in the development and specification of lymphatic vessels of the zebrafish trunk. SUMMARYVasohibin-1 mediated detyrosination of endothelial microtubules is selectively required for adequate behaviour of venous secondary sprouting and subsequent formation of functional lymphatics in the zebrafish trunk.

developmental biology↗

bioRxiv2018

Arterio-Venous Remodeling in the Zebrafish Trunk Is Controlled by Genetic Programming and Flow-Mediated Fine-Tuning

How developing vascular networks acquire the right balance of arteries, veins and lymphatics to efficiently supply and drain tissues is poorly understood [1, 2]. In zebrafish embryos, the robust and regular 50:50 global balance of intersegmental veins and arteries that form along the trunk [3], prompts the intriguing question how the organism keeps \"count\". Previous studies suggest that the ultimate fate of an intersegmental vessel (ISV) is determined by the identity of the approaching secondary sprout emerging from the posterior cardinal vein (PCV) [1, 4-7]. Here, using high time-resolution imaging, advanced cell tracking and computational analysis, we show that the formation of a balanced trunk vasculature involves an early heterogeneity in endothelial cell (EC) behavior in the seemingly identical primary ISVs and an adaptive flow-mediated mechanism that fine-tunes the balance of arteries and veins along the trunk. Detailed examination of the trunk vasculature dynamics throughout development reveals the frequent formation of three-way vascular connections between primary ISVs, the dorsal aorta (DA) and the PCV. Differential resolution of these connections into arteries or veins is mediated by polarized cell movement of the ECs within the ISV. Quantitative analysis of the cellular organization, polarity and directional movement of ECs in primary ISVs identifies an early differential behavior between future arteries and veins that is largely specified in the ECs of the individual ISVs, is dependent on Dll4/Notch, and occurs even in the absence of secondary sprouting. Notch signaling is involved in a local patterning mechanism normally favoring the formation of alternating arteries and veins. The global artery-vein balance is however maintained through a flow-dependent mechanism that can overwrite the local patterning. We propose that this dual mechanism driving arterio-venous identity during developmental angiogenesis in the zebrafish trunk provides the adaptability required to establish a balanced network of arteries, veins and lymphatic vessels.

cell biology↗