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Gembloux Agro-Bio Tech (GxABT)
Gembloux Agro-Bio Tech (GxABT)
MASTER THESIS
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Investigation of the structural constraints on Wnt ligands evolution through mutagenesis

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Roscel, Manon ULiège
Promotor(s) : Vanhollebeke, Benoit ; Willems, Luc ULiège
Date of defense : 26-Aug-2022 • Permalink : http://hdl.handle.net/2268.2/15534
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Title : Investigation of the structural constraints on Wnt ligands evolution through mutagenesis
Translated title : [fr] Investigation des contraintes structurelles sur l'évolution des ligands Wnt par mutagenèse
Author : Roscel, Manon ULiège
Date of defense  : 26-Aug-2022
Advisor(s) : Vanhollebeke, Benoit 
Willems, Luc ULiège
Committee's member(s) : Twizere, Jean-Claude ULiège
Deleu, Magali ULiège
Massart, Sébastien ULiège
Sindic, Marianne ULiège
Language : English
Number of pages : 65
Keywords : [en] Wnt ligands
[en] Mutagenesis
[en] Stability
[en] Wnt
[en] Evolution
Discipline(s) : Life sciences > Biochemistry, biophysics & molecular biology
Research unit : ULB Laboratoire de signalisation neurovasculaire
Target public : Researchers
Institution(s) : Université de Liège, Liège, Belgique
Degree: Master en bioingénieur : chimie et bioindustries, à finalité spécialisée
Faculty: Master thesis of the Gembloux Agro-Bio Tech (GxABT)

Abstract

[en] The Wnt/β-catenin pathway is a signaling pathway that controls many cellular decisions and
behaviors during embryonic and adult development. Dysfunction of this signaling pathway can
lead to diseases. The challenge in treating these diseases is to find specific treatments that act
in a targeted way, without disrupting the Wnt/β-catenin pathway in the rest of the body.
Previous studies have focused specifically on blood-brain barrier (BBB) dysfunction and
therapeutic strategies to treat it. The Wnt7a/b protein is an important signal for the formation
and maintenance of the BBB and could be an interesting therapeutic asset, assuming that it is
specific to the BBB. Martin, M. et al (2022) identified variants in Wnt7a that exhibit specific
agonism for Gpr124/Reck, which is a complex involved in Wnt7a/b signaling at the BBB. These
agonists only activate the Wnt/β-catenin pathway in the presence of the Gpr124/Reck complex,
making them specific to Gpr124/Reck contexts, such as the BBB. Why these agonists lost the
ability to activate the Wnt/β-catenin pathway in the absence of the Gpr124/Reck complex
remains to be determined, and is the aim of this master thesis. The first hypothesis formulated
in this study is based on the relative instability of Gpr124/Reck agonists. The mutation of a
single surface residue in the different agonists could lead to a decrease in the stability of the
proteins, making them too weak to activate signaling in the absence of the stabilizing Reck.
Since the Wnt7a protein is naturally unstable, working on the stability of its agonists is
laborious. The corresponding mutations were therefore introduced in the more stable Wnt3
protein in order to compare the stability of the variants with the wild type (WT) protein. We
show that a prototypical Wnt3 variant is less stable than the Wnt3WT protein, reinforcing the
hypothesis stated by Martin, M. et al (2022). Furthermore, we also document that the Wnt3
variant exerts a dominant negative effect on the WT protein. This dominant-negative effect, the
mechanism of which remains to be explained, was also observed between the Wnt7aWT protein
and one of its agonists. Finally, a divergence between the different Wnt ligands is observed
with respect to the functional importance of the surface residues. Indeed, the point mutation of
an equivalent surface residue will not have the same impact on the different Wnt ligands. The
stability between the Wnt ligands also seems to vary, with Wnt7a proteins being much less
stable than other Wnt ligands such as Wnt1 and Wnt3.


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