Abstract
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.
Highlights
The secreted protein Noggin[1] is a well-known embryonic inducer of the body axis, which is expressed in the Spemann organizer and has a primary function as a BMP antagonist[1,2]
Using CoIP and surface plasmon resonance (SPR) assays, we demonstrated that Noggin[4] binds Wnt[8], which is a principal ligand in Wnt/β-Catenin signalling that regulates the anterior-posterior patterning during gastrulation and neurulation (Fig. 2a; Fig. S6)
We identified secondary head structures, including forebrains with cyclopic eyes, in approximately 60% (n = 70) of the tadpoles co-injected with Noggin[4] mRNA and mRNA of the dominant-negative variant of the BMP receptor, tBR (Fig. 2c,c’)
Summary
The secreted protein Noggin[1] is a well-known embryonic inducer of the body axis, which is expressed in the Spemann organizer and has a primary function as a BMP antagonist[1,2]. It has recently been demonstrated that Noggin[1] and Noggin[2], which have approximately 60% similarity with each other, inhibit BMP and Nodal/Activin and Wnt-beta-catenin signalling[6,7]. These findings indicate that it is important to elucidate the functions of the third sub-family of Noggins, Noggin[4], which comprises members with substantially less homology with other Noggins (approximately 35%) and may exhibit different molecular and physiological activity. By using a specially developed mathematical approach, we directly estimated the constant of Noggin[4] binding to Wnt[8] in living embryos and confirmed that Noggin[4] fine-tunes the Wnt[8] signalling gradient in the anterior region of the embryo
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