Keeping a lid on nodal: transcriptional and translational repression of nodal signalling

Abstract

Nodal is an evolutionarily conserved member of the transforming growth factor-β (TGF-β) superfamily of secreted signalling factors. Nodal factors are known to play key roles in embryonic development and asymmetry in a variety of organisms ranging from hydra and sea urchins to fish, mice and humans. In addition to embryonic patterning, Nodal signalling is required for maintenance of human embryonic stem cell pluripotency and mis-regulated Nodal signalling has been found associated with tumour metastases. Therefore, precise and timely regulation of this pathway is essential. Here, we discuss recent evidence from sea urchins, frogs, fish, mice and humans that show a role for transcriptional and translational repression of Nodal signalling during early development.

Keywords: development; localization; nodal signalling; repression; transcription; translation.

Figure 1.

Schematic of maternal sqt/nodal RNA expression in early zebrafish embryos. Sqt RNA localizes by the four-cell stage in one or two cells, which later form dorsal progenitors, marked by nuclear β-catenin and gsc expression.

Figure 2.

Schematic of sqt DLE sequence and structure motif. (a) Schematic of sqt exon 3 and the 3′-UTR, showing the dorsal localization element (DLE; green shading), which includes a single-stranded motif (pink box) and a short stem-loop structure. (b) The sequence of the single-stranded motif (pink highlighted region) and the stem-loop structure of the hairpin are shown.

Figure 3.

Schematic of zebrafish ybx1 and sqt/nodal mutant phenotypes. In sqt mutants gsc expression is initiated but not maintained, whereas in Mybx1 mutants, sqt RNA is mis-localized and gsc is expressed prematurely in the expanded yolk syncytial layer (YSL). DIC images show the phenotypes of wild-type or mutant embryos.

Figure 4.

Model of translational repression of Nodal pathway components. (a) In early zebrafish embryos, Ybx1 represses squint/nodal translation by binding to the translation pre-initiation complex proteins and the squint DLE (solid blue box). Squint/Nodal translation is activated from late blastula stages by unknown factors. (b) In vegetal cells of frog embryos, Bic-C represses xCR1 translation by binding to the translation pre-initiation complex proteins and the xCR1 TCE (solid green box). In animal cap cells, xCR1 translation is activated in the absence of Bic-C. (c) miRNA-378a-5p (black comb) binds to the 3′-UTR (solid red box) of human Nodal RNA and unknown factors (?) to repress Nodal translation in the human placenta. In the absence of miRNA-378a-5p, nodal translation is activated.