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A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects
Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal do...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9398005/ https://www.ncbi.nlm.nih.gov/pubmed/35951645 http://dx.doi.org/10.1371/journal.pgen.1010335 |
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author | Gagliani, Ellen K. Gutzwiller, Lisa M. Kuang, Yi Odaka, Yoshinobu Hoffmeister, Phillipp Hauff, Stefanie Turkiewicz, Aleksandra Harding-Theobald, Emily Dolph, Patrick J. Borggrefe, Tilman Oswald, Franz Gebelein, Brian Kovall, Rhett A. |
author_facet | Gagliani, Ellen K. Gutzwiller, Lisa M. Kuang, Yi Odaka, Yoshinobu Hoffmeister, Phillipp Hauff, Stefanie Turkiewicz, Aleksandra Harding-Theobald, Emily Dolph, Patrick J. Borggrefe, Tilman Oswald, Franz Gebelein, Brian Kovall, Rhett A. |
author_sort | Gagliani, Ellen K. |
collection | PubMed |
description | Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant. Importantly, genetic studies support a model that heterozygous Drosophila with the AOS-like Su(H) allele behave in an opposing manner to heterozygous flies with a Su(H) null allele, due to a dominant activity of sequestering either the Notch co-activator or the antagonistic Hairless co-repressor. Consistent with this model, AOS-like Su(H) and Rbpj variants have decreased DNA binding activity compared to wild type proteins, but these variants do not significantly alter protein binding to the Notch co-activator or the fly and mammalian co-repressors, respectively. Taken together, these data suggest a cofactor sequestration mechanism underlies AOS phenotypes associated with RBPJ variants, whereby the AOS-associated RBPJ allele encodes a protein with compromised DNA binding activity that retains cofactor binding, resulting in Notch target gene dysregulation. |
format | Online Article Text |
id | pubmed-9398005 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-93980052022-08-24 A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects Gagliani, Ellen K. Gutzwiller, Lisa M. Kuang, Yi Odaka, Yoshinobu Hoffmeister, Phillipp Hauff, Stefanie Turkiewicz, Aleksandra Harding-Theobald, Emily Dolph, Patrick J. Borggrefe, Tilman Oswald, Franz Gebelein, Brian Kovall, Rhett A. PLoS Genet Research Article Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant. Importantly, genetic studies support a model that heterozygous Drosophila with the AOS-like Su(H) allele behave in an opposing manner to heterozygous flies with a Su(H) null allele, due to a dominant activity of sequestering either the Notch co-activator or the antagonistic Hairless co-repressor. Consistent with this model, AOS-like Su(H) and Rbpj variants have decreased DNA binding activity compared to wild type proteins, but these variants do not significantly alter protein binding to the Notch co-activator or the fly and mammalian co-repressors, respectively. Taken together, these data suggest a cofactor sequestration mechanism underlies AOS phenotypes associated with RBPJ variants, whereby the AOS-associated RBPJ allele encodes a protein with compromised DNA binding activity that retains cofactor binding, resulting in Notch target gene dysregulation. Public Library of Science 2022-08-11 /pmc/articles/PMC9398005/ /pubmed/35951645 http://dx.doi.org/10.1371/journal.pgen.1010335 Text en © 2022 Gagliani et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Gagliani, Ellen K. Gutzwiller, Lisa M. Kuang, Yi Odaka, Yoshinobu Hoffmeister, Phillipp Hauff, Stefanie Turkiewicz, Aleksandra Harding-Theobald, Emily Dolph, Patrick J. Borggrefe, Tilman Oswald, Franz Gebelein, Brian Kovall, Rhett A. A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects |
title | A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects |
title_full | A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects |
title_fullStr | A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects |
title_full_unstemmed | A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects |
title_short | A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects |
title_sort | drosophila su(h) model of adams-oliver syndrome reveals cofactor titration as a mechanism underlying developmental defects |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9398005/ https://www.ncbi.nlm.nih.gov/pubmed/35951645 http://dx.doi.org/10.1371/journal.pgen.1010335 |
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