In:
Science, American Association for the Advancement of Science (AAAS), Vol. 375, No. 6582 ( 2022-02-18)
Abstract:
Central nervous system (CNS) endothelial cells establish a selective filter at the interface between the blood and the brain tissue, called the blood-brain barrier (BBB). The BBB is established during early embryogenesis and maintained throughout adulthood by neurovascular communications occurring within functionally integrated neurovascular units. In numerous CNS disorders, these homeostatic neurovascular microenvironments are disrupted, and consequently, excessive infiltrations of fluids, molecules, and cells alter the neuronal milieu and worsen disease outcome. Therapeutic strategies are needed for the restoration of compromised BBB function. RATIONALE An appealing strategy from a therapeutic standpoint is to repair the dysfunctional BBB by using the molecules that endogenously control its formation during embryogenesis. By respecting the developmental molecular logic of the target tissue, such an approach is best positioned to achieve physiological refunctionalization. More so, by focusing on the upstream regulators of BBB development, the likelihood of correctly setting the stage for a productive repair process increases. Wnt7a/b are some of the earliest and best characterized BBB-inducing signals across vertebrates and therefore constitute a priori prime candidates as BBB-repairing agents. Nonetheless, safe therapeutic use of Wnt ligands such as Wnt7a is unlikely because of their pleiotropic Frizzled (Fz) signaling activities and the widespread expression of Fz receptors across cells and tissues. However, at the BBB, Wnt7a/b ligands signal through an atypical receptor complex containing the adhesion G protein–coupled receptor Gpr124 and the glycosylphosphatidylinositol-anchored glycoprotein Reck. We reasoned that this receptor complex, more than the Fz receptors themselves, could be exploited to achieve BBB repair with the required level of specificity. RESULTS Wnt ligands exhibit a conserved two-domain structure, each domain making one functionally important contact with Fz receptors. We discovered that a hemisected Wnt7a, lacking the C-terminal domain and its embedded Fz contact site, retained partial but selective activity on the Gpr124/Reck-containing receptor complexes of the BBB. This specificity provided proof-of-concept evidence that the presence of Gpr124/Reck changes the modalities of Fz-Wnt interactions, and that Wnt7a/b can be used as scaffolds to achieve Gpr124/Reck-specific agonism. Accordingly, a class of highly specific and fully active Gpr124/Reck agonists, differing from Wnt7a by only a single surface-exposed residue, was identified through large-scale mutagenesis. Mechanistically, the selectivity of the uncovered agonists resulted from their strict dependency on Reck and Gpr124 for Fz binding and activation. In contrast to the wild-type Wnt7a ligand or other canonical Wnt ligands, whose overexpression is incompatible with vertebrate development, Gpr124/Reck agonists were well tolerated in vivo, even when delivered ubiquitously during Xenopus or zebrafish early development, or throughout the neonatal mouse brain. Furthermore, Gpr124/Reck agonists exhibited therapeutic efficacy in mouse models of brain tumors and ischemic stroke, where long-lasting BBB normalization was achieved through a single “hit-and-run” intravenous gene delivery. By restoring endothelial Wnt signaling, Gpr124/Reck agonists normalized the BBB pleiotropically, affecting both the transcellular and paracellular permeability pathways. CONCLUSION This work reveals that the signaling specificity of Wnt ligands is adjustable and defines a modality to treat CNS neurological disorders by normalizing BBB function. Such BBB-focused intervention strategies have considerable potential as disease-modifying treatments or as secondary preventive agents in various CNS pathologies, including stroke, multiple sclerosis, epilepsy, and neurodegenerative disorders such as Alzheimer’s disease. Repurposing Wnt7a ligands into BBB therapeutics. BBB dysfunction has been implicated in the etiology of a large set of CNS disorders. Wnt7a/b ligands, which dominate the neurovascular differentiation cascade during vertebrate development, are here repurposed as safe BBB therapeutics by engineering them into highly specific Gpr124/Reck agonists. [Illustration created with BioRender]
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abm4459
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2022
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128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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