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Our data point to the conclusion that strength (defined here as the ultimate number of intracellular domain molecules reaching the nucleus, integrating ligand-mediated release and nuclear translocation) and duration (half life of NICD\/RBPjk\/MAML\/DNA complexes, integrating cooperativity and stability dependent on shared sequence elements) are the factors that underlies much of the differences between Notch1 and Notch2 in all the contexts we examined including T cell development, skin differentiation and carcinogenesis, the inner ear, the lung, and the retina. We were able to show that phenotypes in the heart, endothelium, and marginal zone B cells are attributed to haploinsufficiency but not intracellular domain composition. Tissue-specific differences in NICD stability were most likely caused by alternative scissile bond choices by tissue specific \u03b3-secretase complexes following the ICD swap. Reinterpretation of clinical finding based on our analyses suggests that differences in outcome segregating with Notch1 or Notch2 are likely to reflect outcomes dependent on the overall strength of Notch signals.<\/jats:p>","DOI":"10.1242\/dev.125492","type":"journal-article","created":{"date-parts":[[2015,6,11]],"date-time":"2015-06-11T11:19:38Z","timestamp":1434021578000},"source":"Crossref","is-referenced-by-count":57,"title":["The intracellular domains of Notch1 and 2 are functionally equivalent during development and carcinogenesis"],"prefix":"10.1242","author":[{"given":"Zhenyi","family":"Liu","sequence":"first","affiliation":[{"name":"SAGE Labs, A Horizon Discovery Group Company, St. Louis, Missouri 63146, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Brunskill","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Varnum-Finney","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Minnesota Medical School, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick Y.","family":"Jay","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics and Genetics, Washington University, Saint Louis, Missouri 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irv","family":"Bernstein","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA"},{"name":"Department of Pediatrics, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuru","family":"Morimoto","sequence":"additional","affiliation":[{"name":"Lung Development and Regeneration, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Kopan","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042422530843400_DEV125492C1","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1038\/nature11738","article-title":"Visualization of splenic marginal zone B-cell shuttling and follicular B-cell egress","volume":"493","author":"Arnon","year":"2013","journal-title":"Nature"},{"key":"2021042422530843400_DEV125492C2","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1016\/j.cell.2009.03.025","article-title":"The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis","volume":"137","author":"Benedito","year":"2009","journal-title":"Cell"},{"key":"2021042422530843400_DEV125492C3","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/S0006-291X(02)02705-5","article-title":"Mutations at the P1\u2032 position of Notch1 decrease intracellular domain stability rather than cleavage by gamma-secretase","volume":"299","author":"Blat","year":"2002","journal-title":"Biochem. 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