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The spatiotemporal distribution of ISM1, with high expression in the anterior primitive streak of the chick embryo and the anterior mesendoderm of the mouse embryo, suggested that ISM1 may regulate signaling by the NODAL subfamily of TGB-\u03b2 cytokines that control embryo patterning. We report that ISM1 is an inhibitor of NODAL signaling. ISM1 has little effect on TGF-\u03b21, ACTIVIN-A, or BMP4 signaling but specifically inhibits NODAL-induced phosphorylation of SMAD2. In line with this observation, ectopic ISM1 causes defective left-right asymmetry and abnormal heart positioning in chick embryos. Mechanistically, ISM1 interacts with NODAL ligand and type I receptor ACVR1B through its AMOP domain, which compromises the NODAL\u2013ACVR1B interaction and down-regulates phosphorylation of SMAD2. Therefore, we identify ISM1 as an extracellular antagonist of NODAL and reveal a negative regulatory mechanism that provides greater plasticity for the fine-tuning of NODAL signaling.<\/jats:p>","DOI":"10.1083\/jcb.201801081","type":"journal-article","created":{"date-parts":[[2019,6,6]],"date-time":"2019-06-06T18:05:14Z","timestamp":1559844314000},"page":"2388-2402","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":34,"title":["ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development"],"prefix":"10.1083","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7996-5635","authenticated-orcid":true,"given":"Liliana","family":"Os\u00f3rio","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 1"},{"name":"Shenzhen Institute of Innovation and Research, The University of Hong Kong, Nanshan, Shenzhen, China 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewei","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 1"},{"name":"Shenzhen Institute of Innovation and Research, The University of Hong Kong, Nanshan, Shenzhen, China 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linsheng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 1"},{"name":"Shenzhen Institute of Innovation and Research, The University of Hong Kong, Nanshan, Shenzhen, China 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixin","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 1"},{"name":"Shenzhen Institute of Innovation and Research, The University of Hong Kong, Nanshan, Shenzhen, China 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6367-3320","authenticated-orcid":true,"given":"Carlos","family":"Neideck","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 1"},{"name":"Shenzhen Institute of Innovation and Research, The University of Hong Kong, Nanshan, Shenzhen, China 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6759-3785","authenticated-orcid":true,"given":"Guojun","family":"Sheng","sequence":"additional","affiliation":[{"name":"International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan 3"},{"name":"RIKEN Center for Developmental Biology, Kobe, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7092-8128","authenticated-orcid":true,"given":"Zhongjun","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 1"},{"name":"Shenzhen Institute of Innovation and Research, The University of Hong Kong, Nanshan, Shenzhen, China 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2019,6,6]]},"reference":[{"key":"2023072310122041400_bib1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a009712","article-title":"The thrombospondins","volume":"3","author":"Adams","year":"2011","journal-title":"Cold Spring Harb. 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