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Title: Role of ephrin-B2 signalling in the developing and mature lymphatic vasculature
Author: Vicente, A.
ISNI:       0000 0004 5363 5261
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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The formation of the lymphatic vasculature takes place in two main steps. The first step establishes the lymphatic endothelial cell fate and primitive vascular network during the early stages of development and is controlled by the transcription factor PROX-1. In the second step at late embryonic and postnatal stages the initial lymphatic plexus is remodelled into a hierarchical mature lymphatic network. A key regulator of this process is the transmembrane protein ephrin-B2, a ligand for the Eph family of receptor tyrosine kinases. With the research depicted in this thesis I have focused on understanding the role ephrin-B2 and its receptor EphB4 play during lymphatic development and the underlying molecular mechanisms. Ephrin-B2 and the signalling mediated via its PDZ-binding motif were previously described to be required for lymphatic development. Using constitutive and inducible tissue-specific loss-of-function mouse models I have shown that ephrin-B2 and its PDZ-related signalling are required not only to initiate the process of lymphatic remodelling but also for the maintenance of a mature lymphatic network. Loss of either of them results in immature lymphatic vessels that lack intraluminal valves. In vitro and in vivo experiments suggest that this is due to defects in the regulation of lymphatic endothelial cell cytoskeleton and cell-cell adhesion. Similarly, EphB4 is required for the initial steps of lymphatic remodelling; however, it is dispensable for the maintenance of adult lymphatic network. Finally, I demonstrated that ephrin-B2 and EphB4 are essential regulators of lymphatic sprouting, but this process is not dependent on ephrin-B2 PDZ-binding motif. These data show that ephrin-B2 signalling is required all through lymphatic development but the underlying molecular mechanisms differ between different developmental stages and processes. While the experimental evidence points towards a synergistic role of ephrin-B2 and EphB4 during lymphatic sprouting and initial remodelling, the role of ephrin-B2 in lymphatic maintenance is EphB4- independent. In addition, lymphatic sprouting is, to our knowledge, the first lymphangiogenic process where ephrin-B2 is required in a PDZ-independent manner. To study the lymphatic-specific deletion of ephrin-B2 and EphB4 I used a novel mouse line that drives Cre recombinase expression under the control of Prox1 promoter. While characterising the line, I described a previously unreported expression of Prox1 in the mesenteric veins. This expression was associated with the appearance of Prox1-positive sprouts from the veins and lympho-venous connections that I further analysed by micro computed tomography.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available