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

Kunimasa Ohta, Ayako Ito, Sei Kuriyama, Giuseppe Lupo, Mitsuko Kosaka, Shin Ichi Ohnuma, Shinichi Nakagawa, Hideaki Tanaka

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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 lowdensity lipoprotein receptor-related protein 5/6 and the seven-pass transmembrane protein Frizzled (Fzd), which contains a Wntbinding 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 × 10 -10 M and competing with Wnt2b. In the developing chick eye, TSK is expressed in the ciliary/iris epithelium, whereasWnt2b is expressed in the adjacent anterior rimof 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 upregulation 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.

Original languageEnglish
Pages (from-to)14962-14967
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number36
DOIs
Publication statusPublished - Sep 6 2011

Keywords

  • Eye development
  • Signaling modulator
  • Small leucine-rich proteoglycan

ASJC Scopus subject areas

  • General

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