Editors' ChoiceDevelopment

Precocious Nodal activity

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Sci. Signal.  24 Nov 2015:
Vol. 8, Issue 404, pp. ec349
DOI: 10.1126/scisignal.aad9091

Like other members of the transforming growth factor–β (TGF-β) superfamily, Nodal is synthesized as a propeptide that is cleaved to generate the biologically active ligand, which has key roles in development. Ellis et al. report that the unprocessed form of Nodal has signaling activity in the prechordal mesoderm of the chick embryo, a tissue that is a source of Sonic hedgehog (Shh). Precise regulation of the duration of Shh signaling in the prechordal mesoderm is required for proper development of the overlying ventral forebrain. Nodal and Shh were transiently expressed in the prechordal mesoderm in vivo, and the timing and duration of expression of both genes were recapitulated in explanted tissue. Application of a secreted protein that binds to and inhibits Nodal or an antibody that binds to Nodal reduced Shh expression in prechordal mesoderm explants. In contrast, inhibiting activin receptor-like kinases (ALKs), which bind mature, processed Nodal, did not affect Shh expression. A recombinant form of mouse Nodal that cannot be cleaved (recombinant proNodal) prolonged Shh expression in explants, whereas mature (cleaved) Nodal did not. Experiments with a fibroblast growth factor receptor (FGFR) antagonist indicated that signaling through FGFRs was also required for proper Shh expression in explants and in vivo. Recombinant proNodal, but not mature Nodal, coimmunoprecipitated with FGFR3, but not FGFR1 or FGFR2, from extracts of HEK293T cells expressing these proteins. Experiments with a tagged form of recombinant proNodal revealed an interaction with FGFR3 in vivo. In both explants and in vivo assays, the prolonged expression of Shh in the prechordal mesoderm induced by recombinant proNodal required FGFR3. Additional experiments in explants suggested that the normal reduction of Shh expression in prechordal mesoderm required bone morphogenetic protein (BMP) signaling and that recombinant proNodal prolonged the duration of Shh expression by antagonizing BMP signaling. These results indicate that unprocessed Nodal can signal through FGFR3 to antagonize BMP signaling during early stages of the development of the nervous system.

P. S. Ellis, S. Burbridge, S. Soubes, K. Ohyama, N. Ben-Haim, C. Chen, K. Dale, M. M. Shen, D. Constam, M. Placzek, ProNodal acts via FGFR3 to govern duration of Shh expression in the prechordal mesoderm. Development 142, 3821–3832 (2015). [PubMed]