Noggin4 is a Noggin family secreted protein whose molecular and physiological functions remain unknown. In this study, we 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.

We describe here the expression pattern of Noggin4 during the early development of the chick embryo (Gallus gallus). The expression of this gene starts with the onset of gastrulation (stage HH4), in two bilateral bands along the primitive streak, with a local maximum around Hensen's node. By the end of gastrulation, Noggin4 transcripts are distributed diffusely throughout the epiblast, with the highest concentration in the head ectoderm. Interestingly, the expression of Noggin4 during the first half of gastrulation demonstrates a clear left-right asymmetry in Hensen's node, being much more intensive in its right anterior portion. During neurulation, Noggin4 is expressed mainly in the neuroectoderm, with the most intensive expression in the head and lateral neural folds. In mesoderm derivatives, expression is seen in somites but not in the notochord. In general, primarily ectodermal and diffusive expression of Noggin4 in chick embryo, with a maximum in the anterior neurectoderm, resembles that of its ortholog in Xenopus, which indicates a conservative function of this gene in evolution.

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We demonstrated that the secreted protein Noggin4 from Xenopus laevis was capable of the in vitro binding to the secreted factor Wnt8, one of the ligands of the Wnt/betaCatenin signaling pathway. It was also shown that posttranslational modifications occurring during secretion of these proteins from the embryonic cells were necessary for their effective interaction. Also, we proposed a method for the preparation of physiologically active secreted morphogenic proteins from the intercellular space of the Xenopus laevis embryos.