Activin/Nodal responsiveness and asymmetric expression of a Xenopus nodal-related gene converge on a FAST-regulated module in intron 1

Vertebrate Nodal-related factors play central roles in mesendoderm inductio n and left-right axis specification, but the mechanisms regulating their ex pression are largely unknown. We identify an element in Xnr1 intron 1 that is activated by activin and Vg1, autoactivated by Xnrs, and suppressed by v entral inducers like BMP4. Intron 1 contains three FAST binding sites on wh ich FAST/Smad transcriptional complexes can assemble; these sites are diffe rentially involved in intron 1-mediated reporter gene expression. Interfere nce with FAST function abolishes intron 1 activity, and transcriptional act ivation of Xnrs by activin in embryonic tissue explant assays, identifying FAST as an essential mediator of Xnr autoregulation and/or 'signal relay' f rom activin-like molecules. Furthermore, the mapping of endogenous activato rs of the Xnr1 intronic enhancer within Xenopus embryos agrees well with th e pattern of Xnr1 transcription during embryogenesis. In transgenic mice, X nr1 intron 1 mimics a similarly located enhancer in the mouse nodal gene, a nd directs FAST site-dependent expression in the primitive streak during ga strulation, and unilateral expression during early somitogenesis, The FAST cassette is similar in an ascidian nodal-related gene, suggesting an ancien t origin for this regulatory module. Thus, an evolutionarily conserved intr onic enhancer in Xnr1 is involved in both mesendoderm induction and asymmet ric expression during left-right axis formation.