title: The intracellular domains of Notch1 and Notch2 are functionally equivalent during development and carcinogenesis.
abstract: Although Notch1 and Notch2 are closely related paralogs and function through the same canonical signaling pathway, they contribute to different outcomes in some cell and disease contexts. To understand the basis for these differences, we examined in detail mice in which the Notch intracellular domains (N1ICD and N2ICD) were swapped. Our data indicate 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 underlie many 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 to intracellular domain composition. Tissue-specific differences in NICD stability were most likely caused by alternative scissile bond choices by tissue-specific γ-secretase complexes following the intracellular domain swap. Reinterpretation of clinical findings 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.
authors.affiliation: SAGE Labs, A Horizon Discovery Group Company, St Louis, MO 63146, USA.
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Developmental Biology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Brunskill
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Varnum-Finney
authors.affiliation: Department of Clinical Medicine, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Departments of Pediatrics and Genetics, Washington University, St Louis, MO 63110, USA.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Irv
authors.initials: I
authors.lastname: Bernstein
authors.affiliation: Lung Development and Regeneration, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Morimoto
authors.affiliation: Division of Developmental Biology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA Raphael.kopan@cchmc.org.
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
mesh_terms: D000483:Alleles; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis; D002454:Cell Differentiation; D002469:Cell Separation; D007758:Ear, Inner / Q000196:embryology; D005260:Female; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006330:Heart Defects, Congenital; D006720:Homozygote; D008168:Lung / Q000196:embryology; D008297:Male; D051379:Mice; D010641:Phenotype; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000378:metabolism*; D012160:Retina / Q000196:embryology; D015398:Signal Transduction; D012867:Skin / Q000196:embryology; D012878:Skin Neoplasms / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D059467:Transcriptome
chemical_list: C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D053829:Amyloid Precursor Protein Secretases
keywords: Carcinogenesis; Domain swap; Endothelium; Heart; Marginal zone B cells; Notch