Papers

Peer-reviewed
Sep, 2011

Tsukushi functions as a Wnt signaling inhibitor by competing with Wnt2b for binding to transmembrane protein Frizzled4

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
  • Kunimasa Ohta
  • ,
  • Ayako Ito
  • ,
  • Sei Kuriyama
  • ,
  • Giuseppe Lupo
  • ,
  • Mitsuko Kosaka
  • ,
  • Shin-ichi Ohnuma
  • ,
  • Shinichi Nakagawa
  • ,
  • Hideaki Tanaka

Volume
108
Number
36
First page
14962
Last page
14967
Language
English
Publishing type
Research paper (scientific journal)
DOI
10.1073/pnas.1100513108
Publisher
NATL ACAD SCIENCES

The Wnt signaling pathway is essential for the development of diverse tissues during embryogenesis. Signal transduction is activated by the binding of Wnt proteins to the type I receptor low-density lipoprotein receptor-related protein 5/6 and the seven-pass transmembrane protein Frizzled (Fzd), which contains a Wnt-binding site in the form of a cysteine-rich domain. Known extracellular antagonists of the Wnt signaling pathway can be subdivided into two broad classes depending on whether they bind primarily to Wnt or to low-density lipoprotein receptor-related protein 5/6. We show that the secreted protein Tsukushi (TSK) functions as a Wnt signaling inhibitor by binding directly to the cysteine-rich domain of Fzd4 with an affinity of 2.3 x 10(-10) M and competing with Wnt2b. In the developing chick eye, TSK is expressed in the ciliary/iris epithelium, whereas Wnt2b is expressed in the adjacent anterior rim of the optic vesicle, where it controls the differentiation of peripheral eye structures, such as the ciliary body and iris. TSK overexpression effectively antagonizes Wnt2b signaling in chicken embryonic retinal cells both in vivo and in vitro and represses Wnt-dependent specification of peripheral eye fates. Conversely, targeted inactivation of the TSK gene in mice causes expansion of the ciliary body and up-regulation of Wnt2b and Fzd4 expression in the developing peripheral eye. Thus, we uncover a crucial role for TSK as a Wnt signaling inhibitor that regulates peripheral eye formation.


Link information
DOI
https://doi.org/10.1073/pnas.1100513108
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000294543400051&DestApp=WOS_CPL
ID information
  • DOI : 10.1073/pnas.1100513108
  • ISSN : 0027-8424
  • Web of Science ID : WOS:000294543400051

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