{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:25:59Z","timestamp":1792599959752,"version":"4.5.0"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"36","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,9,6]]},"abstract":"<jats:p>\n                    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\u2013related 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\u2013related 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 \u00d7 10\n                    <jats:sup>\u221210<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1100513108","type":"journal-article","created":{"date-parts":[[2011,8,19]],"date-time":"2011-08-19T22:47:12Z","timestamp":1313794032000},"page":"14962-14967","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":65,"title":["Tsukushi functions as a Wnt signaling inhibitor by competing with Wnt2b for binding to transmembrane protein Frizzled4"],"prefix":"10.1073","volume":"108","author":[{"given":"Kunimasa","family":"Ohta","sequence":"first","affiliation":[{"name":"Department of Developmental Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan;"},{"name":"Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Developmental Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan;"},{"name":"Global Center of Excellence, Kumamoto University, Kumamoto 860-8556, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sei","family":"Kuriyama","sequence":"additional","affiliation":[{"name":"Department of Developmental Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan;"},{"name":"21st Century Center of Excellence, Kumamoto University, Kumamoto 860-8556, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Lupo","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cC. Darwin,\u201d University of Rome \u201cLa Sapienza,\u201d 00185 Rome, Italy;"},{"name":"Istituto Pasteur\u2013Fondazione Cenci Bolognetti, 00185, Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuko","family":"Kosaka","sequence":"additional","affiliation":[{"name":"RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-ichi","family":"Ohnuma","sequence":"additional","affiliation":[{"name":"Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"RIKEN Advanced Science Institute, Nakagawa RNA Biology Laboratory, Saitama 351-0198, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Developmental Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan;"},{"name":"Global Center of Excellence, Kumamoto University, Kumamoto 860-8556, Japan;"},{"name":"21st Century Center of Excellence, Kumamoto University, Kumamoto 860-8556, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,8,19]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.20.010403.113126"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2009.06.016"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2006.11.001"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.033910"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.00623"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2008.05.002"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.17.1.255"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02474"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.21973"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2007.04.052"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.10315"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.06-0403"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2004.08.014"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R800020200"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02579"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02178"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001004"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1159\/000082277"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20621"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1567-133X(03)00107-8"},{"key":"e_1_3_3_21_2","first-page":"470","article-title":"Differential localization of collagen type IX isoform messenger RNAs during early ocular development","volume":"35","author":"Dhawan RR","year":"1994","unstructured":"RR Dhawan, DC Beebe, Differential localization of collagen type IX isoform messenger RNAs during early ocular development. Invest Ophthalmol Vis Sci 35, 470\u2013478 (1994).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01856"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.modgep.2005.04.016"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20303"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(02)00423-9"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207850200"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00216-8"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2443.1998.00221.x"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.10.127"},{"key":"e_1_3_3_30_2","first-page":"75","volume-title":"The Glaucomas","author":"Morrison JC","year":"1996","unstructured":"JC Morrison, EM Van Buskirk, TF Freddo, Anatomy, microcirculation, and ultrastructure of the ciliary body. The Glaucomas, eds R Ritch, MB Shields, T Krupin (Mosby, 2nd Ed, St. Louis), pp. 75\u201388, Chap 3. (1996).","edition":"2"},{"key":"e_1_3_3_31_2","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1002\/dvdy.22072","article-title":"Visualizing canonical Wnt signaling during mouse craniofacial development","volume":"239","author":"Mani P","year":"2010","unstructured":"P Mani, A Jarrell, J Myers, R Atit, Visualizing canonical Wnt signaling during mouse craniofacial development. Dev Dyn 239, 354\u2013363 (2010).","journal-title":"Dev Dyn"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/81627"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/81619"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-0899com"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00244"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1100513108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T05:33:20Z","timestamp":1712727200000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1100513108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,8,19]]},"references-count":35,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2011,9,6]]}},"alternative-id":["10.1073\/pnas.1100513108"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1100513108","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,8,19]]},"assertion":[{"value":"2011-08-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}