Direct action of the Nodal-related signal Cyclops in induction of sonic hedgehog in the ventral midline of the CNS

The secreted molecule Sonic hedgehog (Shh) is crucial for floor plate and v entral brain development in amniote embryos. In zebrafish, mutations in cyc lops (cyc), a gene that encodes a distinct signal related to the TGF beta f amily member Nodal, result in neural tube defects similar to those of shh n ull mice. eye mutant embryos display cyclopia and lack floor plate and vent ral brain regions, suggesting a role for Cyc in specification of these stru ctures. eye mutants express shh in the notochord but lack expression of shh in the ventral brain. Here we show that Cyc signalling can act directly on shh expression in neural tissue. Modulation of the Cyc signalling pathway by constitutive activation or inhibition of Smad2 leads to altered shh expr ession in zebrafish embryos. Ectopic activation of the shh promoter occurs in response to expression of Cyc signal transducers in the chick neural tub e. Furthermore an enhancer of the shh gene, which controls ventral neural t ube expression, is responsive to Cyc signal transducers. Our data imply tha t the Nodal related signal Cyc induces shh expression in the ventral neural tube, Based on the differential responsiveness of shh and other neural tub e specific genes to Hedgehog and Cyc signalling, a two-step model for the e stablishment of the ventral midline of the CNS is proposed.