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A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche
Loss-of-function studies have determined that Notch signaling is essential for hematopoietic and endothelial development. By deleting a single allele of the Notch1 transcriptional activation domain we generated viable, post-natal mice exhibiting hypomorphic Notch signaling. These heterozygous mice,...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ferrata Storti Foundation
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821596/ https://www.ncbi.nlm.nih.gov/pubmed/30923091 http://dx.doi.org/10.3324/haematol.2018.208660 |
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author | Shao, Lijian Sottoriva, Kilian Palasiewicz, Karol Zhang, Jizhou Hyun, James Soni, Sweta S. Paik, Na Yoon Gao, Xiaopei Cuervo, Henar Malik, Asrar B. Rehman, Jalees Lucas, Daniel Pajcini, Kostandin V. |
author_facet | Shao, Lijian Sottoriva, Kilian Palasiewicz, Karol Zhang, Jizhou Hyun, James Soni, Sweta S. Paik, Na Yoon Gao, Xiaopei Cuervo, Henar Malik, Asrar B. Rehman, Jalees Lucas, Daniel Pajcini, Kostandin V. |
author_sort | Shao, Lijian |
collection | PubMed |
description | Loss-of-function studies have determined that Notch signaling is essential for hematopoietic and endothelial development. By deleting a single allele of the Notch1 transcriptional activation domain we generated viable, post-natal mice exhibiting hypomorphic Notch signaling. These heterozygous mice, which lack only one copy of the transcriptional activation domain, appear normal and have no endothelial or hematopoietic phenotype, apart from an inherent, cell-autonomous defect in T-cell lineage development. Following chemotherapy, these hypomorphs exhibited severe pancytopenia, weight loss and morbidity. This phenotype was confirmed in an endothelial-specific, loss-of-function Notch1 model system. Ang1, secreted by hematopoietic progenitors after damage, activated endothelial Tie2 signaling, which in turn enhanced expression of Notch ligands and potentiated Notch1 receptor activation. In our heterozygous, hypomorphic model system, the mutant protein that lacks the Notch1 transcriptional activation domain accumulated in endothelial cells and interfered with optimal activity of the wildtype Notch1 transcriptional complex. Failure of the hypomorphic mutant to efficiently drive transcription of key gene targets such as Hes1 and Myc prolonged apoptosis and limited regeneration of the bone marrow niche. Thus, basal Notch1 signaling is sufficient for niche development, but robust Notch activity is required for regeneration of the bone marrow endothelial niche and hematopoietic recovery. |
format | Online Article Text |
id | pubmed-6821596 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Ferrata Storti Foundation |
record_format | MEDLINE/PubMed |
spelling | pubmed-68215962019-11-05 A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche Shao, Lijian Sottoriva, Kilian Palasiewicz, Karol Zhang, Jizhou Hyun, James Soni, Sweta S. Paik, Na Yoon Gao, Xiaopei Cuervo, Henar Malik, Asrar B. Rehman, Jalees Lucas, Daniel Pajcini, Kostandin V. Haematologica Article Loss-of-function studies have determined that Notch signaling is essential for hematopoietic and endothelial development. By deleting a single allele of the Notch1 transcriptional activation domain we generated viable, post-natal mice exhibiting hypomorphic Notch signaling. These heterozygous mice, which lack only one copy of the transcriptional activation domain, appear normal and have no endothelial or hematopoietic phenotype, apart from an inherent, cell-autonomous defect in T-cell lineage development. Following chemotherapy, these hypomorphs exhibited severe pancytopenia, weight loss and morbidity. This phenotype was confirmed in an endothelial-specific, loss-of-function Notch1 model system. Ang1, secreted by hematopoietic progenitors after damage, activated endothelial Tie2 signaling, which in turn enhanced expression of Notch ligands and potentiated Notch1 receptor activation. In our heterozygous, hypomorphic model system, the mutant protein that lacks the Notch1 transcriptional activation domain accumulated in endothelial cells and interfered with optimal activity of the wildtype Notch1 transcriptional complex. Failure of the hypomorphic mutant to efficiently drive transcription of key gene targets such as Hes1 and Myc prolonged apoptosis and limited regeneration of the bone marrow niche. Thus, basal Notch1 signaling is sufficient for niche development, but robust Notch activity is required for regeneration of the bone marrow endothelial niche and hematopoietic recovery. Ferrata Storti Foundation 2019-11 /pmc/articles/PMC6821596/ /pubmed/30923091 http://dx.doi.org/10.3324/haematol.2018.208660 Text en Copyright© 2019 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher. |
spellingShingle | Article Shao, Lijian Sottoriva, Kilian Palasiewicz, Karol Zhang, Jizhou Hyun, James Soni, Sweta S. Paik, Na Yoon Gao, Xiaopei Cuervo, Henar Malik, Asrar B. Rehman, Jalees Lucas, Daniel Pajcini, Kostandin V. A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche |
title | A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche |
title_full | A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche |
title_fullStr | A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche |
title_full_unstemmed | A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche |
title_short | A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche |
title_sort | tie2-notch1 signaling axis regulates regeneration of the endothelial bone marrow niche |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821596/ https://www.ncbi.nlm.nih.gov/pubmed/30923091 http://dx.doi.org/10.3324/haematol.2018.208660 |
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