arrow encodes an LDL-receptor-related protein essential for Wingless signalling

The Wnt family of secreted molecules functions in cell-fate determination and morphogenesis during development in both vertebrates and invertebrates (reviewed in ref. 1). Drosophila Wingless is a founding member of this family, and many components of its signal transduction cascade have been identified, including the Frizzled class of receptor. But the mechanism by which the Wingless signal is received and transduced across the membrane is not completely understood. Here we describe a gene that is necessary for all Wingless signalling events in Drosophila. We show that arrow gene function is essential in cells receiving Wingless input and that it acts upstream of Dishevelled. arrow encodes a single-pass transmembrane protein, indicating that it may be part of a receptor complex with Frizzled class proteins. Arrow is a low-density lipoprotein (LDL)-receptor-related protein (LRP), strikingly homologous to murine and human LRP5 and LRP6. Thus, our data suggests a new and conserved function for this LRP subfamily in Wingless/Wnt signal reception.

[1]  M. Wehrli,et al.  Epithelial planar polarity in the developing Drosophila eye. , 1995, Development.

[2]  Yoichi Kato,et al.  LDL-receptor-related proteins in Wnt signal transduction , 2000, Nature.

[3]  N. Perrimon,et al.  Autosomal P[ovoD1] dominant female-sterile insertions in Drosophila and their use in generating germ-line chimeras. , 1993, Development.

[4]  T. Curran,et al.  Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS. , 1999, Genes & development.

[5]  F. Hoffmann,et al.  Decapentaplegic restricts the domain of wingless during Drosophila limb patterning , 1996, Nature.

[6]  G. Struhl,et al.  Complementary and Mutually Exclusive Activities of Decapentaplegic and Wingless Organize Axial Patterning during Drosophila Leg Development , 1996, Cell.

[7]  W. Brook,et al.  Antagonistic Interactions Between Wingless and Decapentaplegic Responsible for Dorsal-Ventral Pattern in the Drosophila Leg , 1996, Science.

[8]  C. Neumann,et al.  Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing. , 1997, Development.

[9]  M. Metzker,et al.  Cloning of a novel member of the low-density lipoprotein receptor family. , 1998, Gene.

[10]  T Suzuki,et al.  A new low density lipoprotein receptor related protein, LRP5, is expressed in hepatocytes and adrenal cortex, and recognizes apolipoprotein E. , 1998, Journal of biochemistry.

[11]  R. Nusse,et al.  Mechanisms of Wnt signaling in development. , 1998, Annual review of cell and developmental biology.

[12]  William C. Skarnes,et al.  An LDL-receptor-related protein mediates Wnt signalling in mice , 2000, Nature.

[13]  E. Wieschaus,et al.  Spatial expression of the Drosophila segment polarity gene armadillo is posttranscriptionally regulated by wingless , 1990, Cell.

[14]  M. Wehrli,et al.  Independent regulation of anterior/posterior and equatorial/polar polarity in the Drosophila eye; evidence for the involvement of Wnt signaling in the equatorial/polar axis. , 1998, Development.

[15]  N. Perrimon,et al.  The Drosophila segment polarity gene dishevelled encodes a novel protein required for response to the wingless signal. , 1994, Genes & development.

[16]  R. Nusse,et al.  Wingless Repression of Drosophila frizzled 2 Expression Shapes the Wingless Morphogen Gradient in the Wing , 1998, Cell.

[17]  N. Perrimon,et al.  Specificities of heparan sulphate proteoglycans in developmental processes , 2000, Nature.

[18]  Jeremy Nathans,et al.  A new member of the frizzled family from Drosophila functions as a Wingless receptor , 1996, Nature.

[19]  H. Theisen,et al.  Shaggy and dishevelled exert opposite effects on Wingless and Decapentaplegic expression and on positional identity in imaginal discs. , 1997, Development.

[20]  J. Goldstein,et al.  LDL-receptor structure: Calcium cages, acid baths and recycling receptors , 1997, Nature.

[21]  F. Kafatos,et al.  Functional cDNA libraries from Drosophila embryos. , 1988, Journal of molecular biology.

[22]  C. M. Chen,et al.  Wingless transduction by the Frizzled and Frizzled2 proteins of Drosophila. , 1999, Development.

[23]  S. Dougan,et al.  Drosophila wingless generates cell type diversity among engrailed expressing cells , 1992, Nature.

[24]  D. Weaver,et al.  Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity. , 1998, Biochemical and biophysical research communications.

[25]  G. Struhl,et al.  Direct and Long-Range Action of a Wingless Morphogen Gradient , 1996, Cell.

[26]  T. Yagi,et al.  Proteins of the CNR Family Are Multiple Receptors for Reelin , 1999, Cell.

[27]  N. Perrimon,et al.  Differential Recruitment of Dishevelled Provides Signaling Specificity in the Planar Cell Polarity and Wingless Signaling Pathways in Drosophila, Planar Cell Polarity (pcp) Signaling Is Mediated by the Receptor Frizzled (fz) and Transduced by Dishevelled (dsh). Wingless (wg) Signaling Also Requires , 2022 .

[28]  E. Wieschaus,et al.  Wingless signaling in the Drosophila embryo: zygotic requirements and the role of the frizzled genes. , 1999, Development.