During Drosophila embryogenesis, a cell sheet movement, dorsal closure, allows establishment of the dorsal epidermis. In this morphogenetic process, lateral epithelia undergo a dramatic movement toward the dorsal midline. In the mutant hemipterous (hep), spreading of the epithelia is blocked; in genetically sensitized hep embryos, cell sheet movement can be arrested at any time, indicating hep requirement in maintaining this morphogenetic activity. Further, hep is required for expression in the dorsal epithelium edges of another dorsal closure gene, puckered. The HEP protein is homologous to the Jun kinase kinase (JNKK) group of mitogen-activated protein kinase kinases (MAPKKs). These data suggest that hep functions in a novel Drosophila MAPK pathway, controlling puckered expression and morphogenetic activity of the dorsal epidermis.
We here identify and characterize an extracellular modulator of Hedgehog signaling in Drosophila, Shifted. Shifted is required for high levels of long-range signaling in the developing wing imaginal disc. Surprisingly, shifted encodes the only Drosophila ortholog of the secreted vertebrate protein Wnt Inhibitory Factor-1 (WIF-1), whose known role is to bind to extracellular Wnts and inhibit their activity. However, Shifted does not regulate Hedgehog signaling by affecting Wingless or Wnt signaling. We show instead that Shifted is a secreted protein that acts over a long distance and is required for the normal accumulation of Hh protein and its movement in the wing. Our data further indicate that Shf interacts with Hh and the heparan sulfate proteoglycans. Therefore, we propose that Shf stabilizes the interaction between Hh and the proteoglycans, an unexpected role for a member of the WIF-1 family.
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