A molecular mechanism for Wnt ligand-specific signaling
Marie
I.
Eubelen1,
Naguissa
Bostaille1,
Pauline
Cabochette1,
Anne
Gauquier1,
Patricia
Tebabi1,
Andra-Cristina
Dumitru2,
Melanie
Kohler2,
Philipp
Gut1,
David
Alsteens2,
Didier
Stainier3,
Abel
Garcia Pino1 and
Benoit
Vanhollebeke1*
-
1
Free University of Brussels, Belgium
-
2
Louvain Institute of Biomolecular Science and Technology, Catholic University of Louvain, Belgium
-
3
Max-Planck-Institut für Herz- und Lungenforschung, Germany
Wnt proteins are conserved signaling molecules that have an essential role in regulating diverse processes during embryogenesis and adult tissue homeostasis (1). In vertebrates, there are 19 Wnts that can potentially interact with each of the ten Fz receptors. The elucidation of the 3D structure of the Wnt/CRD complex has revealed that Wnt/Fz interactions are largely dominated by highly conserved residues (2). To date, it remains unknown what mechanism confers the specificity required to a cell to discriminate the different Wnt ligands.
Wnt pathway specificity appears to be in large part determined by the presence of coreceptors at the cell surface. A pertinent example is the exclusive control of mammalian forebrain and ventral spinal cord angiogenesis by Wnt7a and Wnt7b. Specifically, in order to respond to neural progenitor-derived Wnt7 by activating Wnt/β-catenin signaling, endothelial cells must express Gpr124 and Reck (3). In this work, we have determined the molecular mechanism by which Gpr124 and Reck confer Wnt7- specificity during brain angiogenesis. We reveal that Reck decodes Wnt ligands by establishing mono-specific contacts with the highly divergent linker domain of Wnt7. We also reveal that by bridging Gpr124 and Frizzled, Dishevelled recruits Wnt7, via its association with Reck, into dynamic Wnt/Frizzled signalosomes, resulting in increased local concentrations of ligand available for Frizzled signaling.
Acknowledgements
FRIA, FNRS, Welbio, the Queen Elisabeth Medical Foundation (Q.E.M.F.), the Fondation ULB and the Hoguet Foundation.
References
1. MacDonald, B. T. & He, X. (2012); Cold Spring Harb Perspect Biol. 4, a007880
2. Janda C.Y., et al. (2012); Science, 337(6090), 59-64.
A molecular mechanism for Wnt ligand-speci c signaling3. Vanhollebeke, B. et al. (2015); eLife 4, e06489.
Keywords:
Wnt signaling,
Wnt7a/b,
specificity,
Brain angiogenesis,
Gpr124/Reck
Conference:
Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018.
Presentation Type:
e-posters
Topic:
NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE
Citation:
Eubelen
MI,
Bostaille
N,
Cabochette
P,
Gauquier
A,
Tebabi
P,
Dumitru
A,
Kohler
M,
Gut
P,
Alsteens
D,
Stainier
D,
Garcia Pino
A and
Vanhollebeke
B
(2019). A molecular mechanism for Wnt ligand-specific signaling.
Front. Neurosci.
Conference Abstract:
Belgian Brain Congress 2018 — Belgian Brain Council.
doi: 10.3389/conf.fnins.2018.95.00097
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Received:
31 Aug 2018;
Published Online:
17 Jan 2019.
*
Correspondence:
PhD. Benoit Vanhollebeke, Free University of Brussels, Brussels, Belgium, benoit.vanhollebeke@ulb.ac.be