Noggin4 is a long-range inhibitor of Wnt8 (not BMP) signalling that regulates head development in Xenopus laevis

Fedor M. Eroshkin, Alexey M. Nesterenko, Alexander V. Borodulin, Natalia Yu. Martynova, Galina V. Ermakova, Fatima K. Gyoeva, Eugeny E. Orlov, Alexey A. Belogurov, Konstantin A. Lukyanov, Andrey V. Bayramov & Andrey G. Zaraisky

Scientific Reports 6, Article number: 23049 (2016)
doi:10.1038/srep23049

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Abstract

Noggin4 is a Noggin family secreted protein whose molecular and physiological functions remain unknown. In this study, Eroshkin et al. demonstrate that in contrast to other Noggins, Xenopus laevis Noggin4 cannot antagonise BMP signalling; instead, it specifically binds to Wnt8 and inhibits the Wnt/β -catenin pathway. Live imaging demonstrated that Noggin4 diffusivity in embryonic tissues significantly exceeded that of other Noggins. Using the Fluorescence Recovery After Photobleaching (FRAP) assay and mathematical modelling, we directly estimated the affinity of Noggin4 for Wnt8 in living embryos and determined that Noggin4 fine-tune the Wnt8 posterior-to-anterior gradient. Our results suggest a role for Noggin4 as a unique, freely diffusing, long-range inhibitor of canonical Wnt signalling, thus explaining its ability to promote head development.

Highlights

• diffuse anterior neural expression of noggin4 at neurula stages - different than noggin1 and noggin2
• injection of noggin4 at early blastula stages does not induce secondary axis formation
• noggin4 binds to and antagonizes wnt8
• noggin4 has a greater membrane diffusion rate compared to noggin1 and noggin2
• noggin4 interaction with wnt8 is hampered by heparin sulfate proteoglycan
• gain and loss of function of noggin4 positively and negatively regulates head specification genes, respectively

Adapted with permission from Macmillan Publishers Ltd: Eroshkin et al. (2016).Noggin4 is a long-range inhibitor of Wnt8 signalling that regulates head development in Xenopus laevis.Scientific Reports 6, Article number: 23049 (2016), doi:10.1038/srep23049, copyright (2016).