Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development
The molecular basis of Wnt-Frizzled specificity is a central question in developmental biology. Reck, a multi-domain and multi-functional glycosylphosphatidylinositol-anchored protein, specifically enhances beta-catenin signaling by Wnt7a and Wnt7b in cooperation with the 7-transmembrane protein Gpr...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/47300 |
| _version_ | 1811199729212588032 |
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| author | Chris Cho Yanshu Wang Philip M Smallwood John Williams Jeremy Nathans |
| author_facet | Chris Cho Yanshu Wang Philip M Smallwood John Williams Jeremy Nathans |
| author_sort | Chris Cho |
| collection | DOAJ |
| description | The molecular basis of Wnt-Frizzled specificity is a central question in developmental biology. Reck, a multi-domain and multi-functional glycosylphosphatidylinositol-anchored protein, specifically enhances beta-catenin signaling by Wnt7a and Wnt7b in cooperation with the 7-transmembrane protein Gpr124. Among amino acids that distinguish Wnt7a and Wnt7b from other Wnts, two clusters are essential for signaling in a Reck- and Gpr124-dependent manner. Both clusters are far from the site of Frizzled binding: one resides at the amino terminus and the second resides in a protruding loop. Within Reck, the fourth of five tandem repeats of an unusual domain with six-cysteines (the CC domain) is essential for Wnt7a stimulation: substitutions P256A and W261A in CC4 eliminate this activity without changing protein abundance or surface localization. Mouse embryos carrying ReckP256A,W261A have severe defects in forebrain angiogenesis, providing the strongest evidence to date that Reck promotes CNS angiogenesis by specifically stimulating Wnt7a and Wnt7b signaling. |
| first_indexed | 2024-04-12T01:52:15Z |
| format | Article |
| id | doaj.art-0242222a5b38491282a86025f3cfb099 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:52:15Z |
| publishDate | 2019-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0242222a5b38491282a86025f3cfb0992022-12-22T03:52:53ZengeLife Sciences Publications LtdeLife2050-084X2019-06-01810.7554/eLife.47300Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular developmentChris Cho0https://orcid.org/0000-0002-0929-6536Yanshu Wang1Philip M Smallwood2John Williams3Jeremy Nathans4https://orcid.org/0000-0001-8106-5460Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United StatesThe molecular basis of Wnt-Frizzled specificity is a central question in developmental biology. Reck, a multi-domain and multi-functional glycosylphosphatidylinositol-anchored protein, specifically enhances beta-catenin signaling by Wnt7a and Wnt7b in cooperation with the 7-transmembrane protein Gpr124. Among amino acids that distinguish Wnt7a and Wnt7b from other Wnts, two clusters are essential for signaling in a Reck- and Gpr124-dependent manner. Both clusters are far from the site of Frizzled binding: one resides at the amino terminus and the second resides in a protruding loop. Within Reck, the fourth of five tandem repeats of an unusual domain with six-cysteines (the CC domain) is essential for Wnt7a stimulation: substitutions P256A and W261A in CC4 eliminate this activity without changing protein abundance or surface localization. Mouse embryos carrying ReckP256A,W261A have severe defects in forebrain angiogenesis, providing the strongest evidence to date that Reck promotes CNS angiogenesis by specifically stimulating Wnt7a and Wnt7b signaling.https://elifesciences.org/articles/47300canonical Wnt signalingGpr124ReckWnt7blood-brain barrierCNS angiogenesis |
| spellingShingle | Chris Cho Yanshu Wang Philip M Smallwood John Williams Jeremy Nathans Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development eLife canonical Wnt signaling Gpr124 Reck Wnt7 blood-brain barrier CNS angiogenesis |
| title | Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development |
| title_full | Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development |
| title_fullStr | Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development |
| title_full_unstemmed | Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development |
| title_short | Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development |
| title_sort | molecular determinants in frizzled reck and wnt7a for ligand specific signaling in neurovascular development |
| topic | canonical Wnt signaling Gpr124 Reck Wnt7 blood-brain barrier CNS angiogenesis |
| url | https://elifesciences.org/articles/47300 |
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