RECK in Neural Precursor Cells Plays a Critical Role in Mouse Forebrain Angiogenesis

Li, Huiping; Miki, Takao; Almeida, Glícia Maria de; Hanashima, Carina; Matsuzaki, Tomoko; Kuo, Calvin J.; Watanabe, Naoki; Noda, Makoto

doi:10.1016/j.isci.2019.08.009

Cited by 13 publications

(6 citation statements)

References 60 publications

(123 reference statements)

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“…Wnt ligands are indeed short-lived and rapidly lose activity by oligomerization, in a process that increases their hydrosolubility ( 22 , 23 ). Reck has been shown to extend the half-life of Wnt7a activity by maintaining it in a monomeric, hydrophobic state ( 20 , 24 ). It is thus possible that the introduction of single-residue variations into Wnt7a reduces ligand stability below a threshold required for Fz signaling, a property that the stabilizing action of Reck could counteract.…”

Section: Gpr124/reck Agonists Require Reck To Bind Fzmentioning

confidence: 99%

Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders

Martin

Vermeiren

Bostaille

et al. 2022

Science

106

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The blood-brain barrier (BBB) protects the central nervous system (CNS) from harmful blood-borne factors. Although BBB dysfunction is a hallmark of several neurological disorders, therapies to restore BBB function are lacking. An attractive strategy is to repurpose developmental BBB regulators, such as Wnt7a, into BBB-protective agents. However, safe therapeutic use of Wnt ligands is complicated by their pleiotropic Frizzled signaling activities. Taking advantage of the Wnt7a/b-specific Gpr124/Reck co-receptor complex, we genetically engineered Wnt7a ligands into BBB-specific Wnt activators. In a “hit-and-run” adeno-associated virus–assisted CNS gene delivery setting, these new Gpr124/Reck-specific agonists protected BBB function, thereby mitigating glioblastoma expansion and ischemic stroke infarction. This work reveals that the signaling specificity of Wnt ligands is adjustable and defines a modality to treat CNS disorders by normalizing the BBB.

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Section: Gpr124/reck Agonists Require Reck To Bind Fzmentioning

confidence: 99%

Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders

Martin

Vermeiren

Bostaille

et al. 2022

Science

106

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“…The stimulatory activity exhibits striking ligand specificity: in transfected cells, stimulation is limited to WNT7A and WNT7B, with no measurable effect on signaling by any of the other 17 mammalian WNTs or by NORRIN (a cystine-knot growth factor and a BETA-CATENIN signaling activator). Interestingly, normal CNS angiogenesis requires Reck expression in both ECs and developing neural cells, as determined by cell type-specific gene deletion of a floxed Reck allele (12,16).…”

mentioning

confidence: 99%

Structure of the RECK CC domain, an evolutionary anomaly

Hsieh

Smallwood

Gabelli

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Five small protein domains, the CC-domains, at the N terminus of the RECK protein, play essential roles in signaling by WNT7A and WNT7B in the context of central nervous system angiogenesis and blood–brain barrier formation and maintenance. We have determined the structure of CC domain 4 (CC4) at 1.65-Å resolution and find that it folds into a compact four-helix bundle with three disulfide bonds. The CC4 structure, together with homology modeling of CC1, reveals the surface locations of critical residues that were shown in previous mutagenesis studies to mediate GPR124 binding and WNT7A/WNT7B recognition and signaling. Surprisingly, sequence and structural homology searches reveal no other cell-surface or secreted domains in vertebrates that resemble the CC domain, a pattern that is in striking contrast to other ancient and similarly sized domains, such as Epidermal Growth Factor, Fibronectin Type 3, Immunoglobulin, and Thrombospondin type 1 domains, which are collectively present in hundreds of proteins.

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“…Analogous non-linear effects on CNS barrier integrity have been observed with different combinations of loss-of-function mutations in WNT7A/WNT7B and NORRIN signaling components (Wang et al, 2018). One mechanistic explanation for the apparently greater reliance of WNT7A/ WNT7B signaling on RECK than on GPR124 could relate to the additional role that RECK plays in WNT7A/WNT7B trafficking, with RECK apparently acting as a chaperone to increase the transport of bioactive WNT7A and WNT7B (Li et al, 2019;Martin et al, 2022).…”

Section: Discussionmentioning

confidence: 84%

The WNT7A/WNT7B/GPR124/RECK signaling module plays an essential role in mammalian limb development

Wang

Venkatesh

et al. 2022

Development

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In central nervous system vascular endothelial cells, signaling via the partially redundant ligands WNT7A and WNT7B requires two co-activator proteins, GPR124 and RECK. WNT7A and RECK have been shown previously to play a role in limb development, but the mechanism of RECK action in this context is unknown. The roles of WNT7B and GPR124 in limb development have not been investigated. Using combinations of conventional and/or conditional loss-of-function alleles for mouse Wnt7a, Wnt7b, Gpr124 and Reck, including a Reck allele that codes for a protein that is specifically defective in WNT7A/WNT7B signaling, we show that reductions in ligand and/or co-activator function synergize to cause reduced and dysmorphic limb bone growth. Two additional limb phenotypes – loss of distal Lmx1b expression and ectopic growth of nail-like structures – occur with reduced Wnt7a/Wnt7b gene copy number and, respectively, with Reck mutations and with combined Reck and Gpr124 mutations. A third limb phenotype – bleeding into a digit – occurs with the most severe combinations of Wnt7a/Wnt7b, Reck and Gpr124 mutations. These data imply that the WNT7A/WNT7B-FRIZZLED-LRP5/LRP6-GPR124-RECK signaling system functions as an integral unit in limb development.

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RECK in Neural Precursor Cells Plays a Critical Role in Mouse Forebrain Angiogenesis

Cited by 13 publications

References 60 publications

Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders

Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders

Structure of the RECK CC domain, an evolutionary anomaly

The WNT7A/WNT7B/GPR124/RECK signaling module plays an essential role in mammalian limb development

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