The core components of the Hedgehog (Hh) signaling pathway—the ligand Hh, its receptor Patched (Ptc), the seven-transmembrane protein Smoothened (Smo), the Gli transcription factors, and the Gli repressor Suppressor of Fused (SuFu)—are conserved from flies to mouse, but the requirement for additional components, particularly those involved in ciliogenesis and intraflagellar transport, varies between species. Rink et al. report that, in the planarian Schmidtea mediterranea, Hh signaling is required for anteroposterior (AP) patterning during regeneration but does not depend on cilia. Genes encoding the planarian homologs of Hh, Ptc, Smo, SuFu, and a Gli transcription factor were expressed in various tissues, suggesting that, as in flies and vertebrates, Hh signaling plays diverse roles. Given its role in developmental patterning events in other species, the authors investigated the role of Hh signaling in planarian regeneration. In regenerating animals fed double-stranded RNA (dsRNA) for hh, smo, or gli1, anterior regeneration was normal, but posterior regeneration was defective both morphologically and by gene expression criteria. Conversely, in regenerating animals fed dsRNA for ptc or sufu, which encode negative regulators of Hh signaling, posterior regeneration was normal and anterior regeneration was defective—the most severely affected animals formed tail tissue in place of a head. Severity of the regeneration phenotypes varied with the dsRNA dosage and was similar to that previously reported for Wnt signaling mutants, in which the highest amount of signaling favors posterior fate and low or no signaling promotes anterior fate. RNAi experiments revealed that Wnt and Hh signaling functioned synergistically in AP patterning and suggested that Hh signaling may regulate expression of genes encoding Wnt ligands. The kinase Fused and kinesin Kif7/27, but not cilia, are required for Hh signaling in the fly; cilia and Kif7/27, but not Fused, are required for Hh signaling in mouse; and Fused, Kif7/27, cilia, and the zinc finger protein Iguana are all required for Hh signaling in zebrafish. The authors determined that Fused, Kif7/27, and Iguana were required for the formation and maintenance of normal cilia, but not for Hh signaling, suggesting that the ancestral function of these proteins is in ciliogenesis. The close association between Hh signaling components and cilia therefore is likely an ancestral character that has been lost in some lineages.
J. C. Rink, K. A. Gurley, S. A. Elliott, A. Sánchez Alvarado, Planarian Hh signaling regulates regeneration polarity and links Hh pathway evolution to cilia. Science 326, 1406–1410 (2009). [Abstract] [Full Text]