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

Pavel Krejci¹  Nicole H. Cernohorsky¹  Vitezslav Bryja²  Tomasz Radaszkiewicz³  Zankruti Dave³  Ondrej Bernatik³  Martin Behal³  Annika Mahl⁴  Florian Witte⁴  Sigmar Stricker⁴ 

[1] Department of Biology, Faculty of Medicine, Masaryk UniversityBrno, Czechia;Department of Cytokinetics, Institute of Biophysics AS CR, v.v.i.Brno, Czechia;Faculty of Sciences, Institute of Experimental Biology, Masaryk UniversityBrno, Czechia;Institute for Chemistry and Biochemistry, Freie Universität BerlinBerlin, Germany;

关键词: noggin;    Wnt5a;    non-canonical Wnt pathways;    BMP signaling;    brachydactyly;    Ror2;   

DOI  :  10.3389/fcell.2017.00047

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown