From Hedgehog Facilitator to Wnt Inhibitor

Abstract

A regulatory protein that controls Wnt signaling in humans appears to have switched jobs during the course of evolution. Two papers reporting studies in flies suggest that Wnt inhibitory factor (WIF) first had an opposite role in regulation of Hedgehog signaling. The Wnt and Hedgehog (Hh) pathways are major signaling pathways that control development and are implicated in human disease. One layer of regulation of the Wnt pathway in humans is mediated by WIF, a protein that acts extracellularly to bind secreted Wnt proteins, thus inhibiting signaling by preventing interaction of Wnts with their receptors. However, this aspect of control over Wnt signaling is missing in Drosophila . Gorfinkiel et al. and Glise et al. studied the Drosophila ortholog of WIF, called Shifted (Shf), and found that it had no effect on Wnt signaling. Instead, Shf was necessary for Hh signaling. Shf mutants showed defects similar to those in flies with mutations in the Hh pathway. Hh normally diffuses from the cells that make it into neighboring cells, and this process was blocked in shf mutants. Fluorescently tagged Shf localized with secreted Hh and the proteins could be immunoprecipitated together from transfected cells. Heparin sulfate proteoglycans, which also aid in transport of Hh, also appear to interact with Shf. It seems that the WIF-1 or Shf protein is even more versatile: Expression of the zebrafish ortholog in flies affected neither Wnt nor Hh signaling. N. Gorfinkiel, J. Sierra, A. Callejo, C. Ibañez, I. Guerrero, The Drosophila ortholog of the human Wnt inhibitor factor Shifted controls the diffusion of lipid-modified Hedgehog. Dev. Cell 8 , 241-253 (2005). [PubMed] B. Glise, C. A. Miller, M. Crozatier, M. A. Halbisen, S. Wise, D. J. Olson, A. Vincent, S. S. Blair, Shifted, the Drosophila ortholog of Wnt Inhibitory Factor-1, controls the distribution and movement of Hedgehog. Dev. Cell 8 , 255-266 (2005). [PubMed]