title: Sfrp1 and Sfrp2 are not involved in Wnt/β-catenin signal silencing during lens induction but are required for maintenance of Wnt/β-catenin signaling in lens epithelial cells.
abstract: During eye lens development, regulation of Wnt/β-catenin signaling is critical for two major processes: initially it must be silent in the lens placode for lens development to proceed, but subsequently it is required for maintenance of the lens epithelium. It is not known how these different phases of Wnt/β-catenin activity/inactivity are regulated. Secreted frizzled related protein-2 (Sfrp2), a putative Wnt-Fz antagonist, is expressed in lens placode and in lens epithelial cells and has been put forward as a candidate for regional Wnt/β-catenin pathway regulation. Here we show its closely-related isoform, Sfrp1, has a complimentary pattern of expression in the lens, being absent from the placode and epithelium but expressed in the fibers. As mice with single knockouts of Sfrp1 or Sfrp2 had no defects in lens formation, we examined lenses of Sfrp1 and Sfrp2 double knockout (DKO) mice and showed that they formed lens placode and subsequent lens structures. Consistent with this we did not observe ectopic TCF/Lef activity in lens placode of DKOs. This indicates that Sfrp1 and Sfrp2 individually, or together, do not constitute the putative negative regulator that blocks Wnt/β-catenin signaling during lens induction. In contrast, Sfrp1 and Sfrp2 appear to have a positive regulatory function because Wnt/β-catenin signaling in lens epithelial cells was reduced in Sfrp1 and Sfrp2 DKO mice. Lenses that formed in DKO mice were smaller than controls and exhibited a deficient epithelium. Thus Sfrps play a role in lens development, at least in part, by regulating aspects of Wnt/β-catenin signaling in lens epithelial cells.
authors.affiliation: Save Sight Institute, The University of Sydney, Australia.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shelley
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.forename: Richard J W
authors.initials: RJ
authors.lastname: Stump
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shimono
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Lovicu
authors.forename: John W
authors.initials: JW
authors.lastname: McAvoy
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D017931:DNA Primers; D004847:Epithelial Cells / Q000166:cytology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007908:Lens, Crystalline / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C491628:Sfrp2 protein, mouse
keywords: Lens development; Lens epithelial cells; Secreted frizzled-related protein; TCF/Lef activity; Wnt/β-catenin