A Novel Role for the BMP Antagonist Noggin in Sensitizing Cells to Non-canonical Wnt-5a/Ror2/Disheveled Pathway Activation
Mammalian limb development is driven by the integrative input from several signaling pathways; a failure to receive or a misinterpretation of these signals results in skeletal defects. The brachydactylies, a group of overlapping inherited human hand malformation syndromes, are mainly caused by mutat...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-05-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fcell.2017.00047/full |
| _version_ | 1818548120330436608 |
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| author | Ondrej Bernatik Tomasz Radaszkiewicz Martin Behal Zankruti Dave Florian Witte Annika Mahl Nicole H. Cernohorsky Pavel Krejci Pavel Krejci Sigmar Stricker Vitezslav Bryja Vitezslav Bryja |
| author_facet | Ondrej Bernatik Tomasz Radaszkiewicz Martin Behal Zankruti Dave Florian Witte Annika Mahl Nicole H. Cernohorsky Pavel Krejci Pavel Krejci Sigmar Stricker Vitezslav Bryja Vitezslav Bryja |
| author_sort | Ondrej Bernatik |
| collection | DOAJ |
| description | Mammalian limb development is driven by the integrative input from several signaling pathways; a failure to receive or a misinterpretation of these signals results in skeletal defects. The brachydactylies, a group of overlapping inherited human hand malformation syndromes, are mainly caused by mutations in BMP signaling pathway components. Two closely related forms, Brachydactyly type B2 (BDB2) and BDB1 are caused by mutations in the BMP antagonist Noggin (NOG) and the atypical receptor tyrosine kinase ROR2 that acts as a receptor in the non-canonical Wnt pathway. Genetic analysis of Nog and Ror2 functional interaction via crossing Noggin and Ror2 mutant mice revealed a widening of skeletal elements in compound but not in any of the single mutants, thus indicating genetic interaction. Since ROR2 is a non-canonical Wnt co-receptor specific for Wnt-5a we speculated that this phenotype might be a result of deregulated Wnt-5a signaling activation, which is known to be essential for limb skeletal elements growth and patterning. We show that Noggin potentiates activation of the Wnt-5a-Ror2-Disheveled (Dvl) pathway in mouse embryonic fibroblast (MEF) cells in a Ror2-dependent fashion. Rat chondrosarcoma chondrocytes (RCS), however, are not able to respond to Noggin in this fashion unless growth arrest is induced by FGF2. In summary, our data demonstrate genetic interaction between Noggin and Ror2 and show that Noggin can sensitize cells to Wnt-5a/Ror2-mediated non-canonical Wnt signaling, a feature that in cartilage may depend on the presence of active FGF signaling. These findings indicate an unappreciated function of Noggin that will help to understand BMP and Wnt/PCP signaling pathway interactions. |
| first_indexed | 2024-12-12T08:15:42Z |
| format | Article |
| id | doaj.art-bbc91f6ed33d474ab4133e9fc106f78d |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-12T08:15:42Z |
| publishDate | 2017-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-bbc91f6ed33d474ab4133e9fc106f78d2022-12-22T00:31:36ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2017-05-01510.3389/fcell.2017.00047256049A Novel Role for the BMP Antagonist Noggin in Sensitizing Cells to Non-canonical Wnt-5a/Ror2/Disheveled Pathway ActivationOndrej Bernatik0Tomasz Radaszkiewicz1Martin Behal2Zankruti Dave3Florian Witte4Annika Mahl5Nicole H. Cernohorsky6Pavel Krejci7Pavel Krejci8Sigmar Stricker9Vitezslav Bryja10Vitezslav Bryja11Faculty of Sciences, Institute of Experimental Biology, Masaryk UniversityBrno, CzechiaFaculty of Sciences, Institute of Experimental Biology, Masaryk UniversityBrno, CzechiaFaculty of Sciences, Institute of Experimental Biology, Masaryk UniversityBrno, CzechiaFaculty of Sciences, Institute of Experimental Biology, Masaryk UniversityBrno, CzechiaInstitute for Chemistry and Biochemistry, Freie Universität BerlinBerlin, GermanyInstitute for Chemistry and Biochemistry, Freie Universität BerlinBerlin, GermanyDepartment of Biology, Faculty of Medicine, Masaryk UniversityBrno, CzechiaFaculty of Sciences, Institute of Experimental Biology, Masaryk UniversityBrno, CzechiaDepartment of Biology, Faculty of Medicine, Masaryk UniversityBrno, CzechiaInstitute for Chemistry and Biochemistry, Freie Universität BerlinBerlin, GermanyFaculty of Sciences, Institute of Experimental Biology, Masaryk UniversityBrno, CzechiaDepartment of Cytokinetics, Institute of Biophysics AS CR, v.v.i.Brno, CzechiaMammalian limb development is driven by the integrative input from several signaling pathways; a failure to receive or a misinterpretation of these signals results in skeletal defects. The brachydactylies, a group of overlapping inherited human hand malformation syndromes, are mainly caused by mutations in BMP signaling pathway components. Two closely related forms, Brachydactyly type B2 (BDB2) and BDB1 are caused by mutations in the BMP antagonist Noggin (NOG) and the atypical receptor tyrosine kinase ROR2 that acts as a receptor in the non-canonical Wnt pathway. Genetic analysis of Nog and Ror2 functional interaction via crossing Noggin and Ror2 mutant mice revealed a widening of skeletal elements in compound but not in any of the single mutants, thus indicating genetic interaction. Since ROR2 is a non-canonical Wnt co-receptor specific for Wnt-5a we speculated that this phenotype might be a result of deregulated Wnt-5a signaling activation, which is known to be essential for limb skeletal elements growth and patterning. We show that Noggin potentiates activation of the Wnt-5a-Ror2-Disheveled (Dvl) pathway in mouse embryonic fibroblast (MEF) cells in a Ror2-dependent fashion. Rat chondrosarcoma chondrocytes (RCS), however, are not able to respond to Noggin in this fashion unless growth arrest is induced by FGF2. In summary, our data demonstrate genetic interaction between Noggin and Ror2 and show that Noggin can sensitize cells to Wnt-5a/Ror2-mediated non-canonical Wnt signaling, a feature that in cartilage may depend on the presence of active FGF signaling. These findings indicate an unappreciated function of Noggin that will help to understand BMP and Wnt/PCP signaling pathway interactions.http://journal.frontiersin.org/article/10.3389/fcell.2017.00047/fullnogginWnt5anon-canonical Wnt pathwaysBMP signalingbrachydactylyRor2 |
| spellingShingle | Ondrej Bernatik Tomasz Radaszkiewicz Martin Behal Zankruti Dave Florian Witte Annika Mahl Nicole H. Cernohorsky Pavel Krejci Pavel Krejci Sigmar Stricker Vitezslav Bryja Vitezslav Bryja A Novel Role for the BMP Antagonist Noggin in Sensitizing Cells to Non-canonical Wnt-5a/Ror2/Disheveled Pathway Activation Frontiers in Cell and Developmental Biology noggin Wnt5a non-canonical Wnt pathways BMP signaling brachydactyly Ror2 |
| title | A Novel Role for the BMP Antagonist Noggin in Sensitizing Cells to Non-canonical Wnt-5a/Ror2/Disheveled Pathway Activation |
| title_full | A Novel Role for the BMP Antagonist Noggin in Sensitizing Cells to Non-canonical Wnt-5a/Ror2/Disheveled Pathway Activation |
| title_fullStr | A Novel Role for the BMP Antagonist Noggin in Sensitizing Cells to Non-canonical Wnt-5a/Ror2/Disheveled Pathway Activation |
| title_full_unstemmed | A Novel Role for the BMP Antagonist Noggin in Sensitizing Cells to Non-canonical Wnt-5a/Ror2/Disheveled Pathway Activation |
| title_short | A Novel Role for the BMP Antagonist Noggin in Sensitizing Cells to Non-canonical Wnt-5a/Ror2/Disheveled Pathway Activation |
| title_sort | novel role for the bmp antagonist noggin in sensitizing cells to non canonical wnt 5a ror2 disheveled pathway activation |
| topic | noggin Wnt5a non-canonical Wnt pathways BMP signaling brachydactyly Ror2 |
| url | http://journal.frontiersin.org/article/10.3389/fcell.2017.00047/full |
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