title: GPR124 functions as a WNT7-specific coactivator of canonical β-catenin signaling.
abstract: G protein-coupled receptor 124 (GPR124) is an orphan receptor in the adhesion family of GPCRs, and previous global or endothelial-specific disruption of Gpr124 in mice led to defective CNS angiogenesis and blood-brain barriergenesis. Similar developmental defects were observed following dual deletion of Wnt7a/Wnt7b or deletion of β-catenin in endothelial cells, suggesting a possible relationship between GPR124 and canonical WNT signaling. Here, we show using in vitro reporter assays, mutation analysis, and genetic interaction studies in vivo that GPR124 functions as a WNT7A/WNT7B-specific costimulator of β-catenin signaling in brain endothelium. WNT7-stimulated β-catenin signaling was dependent upon GPR124's intracellular PDZ binding motif and a set of leucine-rich repeats in its extracellular domain. This study reveals a vital role for GPR124 in potentiation of WNT7-induced canonical β-catenin signaling with important implications for understanding and manipulating CNS-specific angiogenesis and blood-brain barrier-genesis.
authors.affiliation: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health (NIH), Frederick, MD 21702, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Posokhova
authors.affiliation: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health (NIH), Frederick, MD 21702, USA.
authors.forename: Animesh
authors.initials: A
authors.lastname: Shukla
authors.affiliation: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health (NIH), Frederick, MD 21702, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Seaman
authors.affiliation: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health (NIH), Frederick, MD 21702, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Volate
authors.affiliation: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health (NIH), Frederick, MD 21702, USA; Basic Research Program, Frederick National Laboratory for Cancer Research (FNLCR), Leidos, Inc., Frederick, MD 21702, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Hilton
authors.affiliation: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health (NIH), Frederick, MD 21702, USA.
authors.forename: Bofan
authors.initials: B
authors.lastname: Wu
authors.affiliation: Transgenic Core Facility, MCGP, NCI, Frederick, MD 21702, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Morris
authors.affiliation: Transgenic Core Facility, MCGP, NCI, Frederick, MD 21702, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Swing
authors.affiliation: Laboratory of Proteomics and Analytical Technologies, FNLCR, Leidos, Inc., Frederick, MD 21702, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health (NIH), Frederick, MD 21702, USA.
authors.forename: Enrique
authors.initials: E
authors.lastname: Zudaire
authors.affiliation: Laboratory of Cellular and Molecular Biology, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Rubin
authors.affiliation: Tumor Angiogenesis Section, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI) at Frederick, National Institutes of Health (NIH), Frederick, MD 21702, USA. Electronic address: stcroix@ncifcrf.gov.
authors.forename: Brad
authors.initials: B
authors.lastname: St Croix
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054731:PDZ Domains; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C554106:GPR124 protein, mouse; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse; C095937:Wnt7b protein, mouse; D051176:beta Catenin