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The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells

Notch1 is required to generate the earliest embryonic hematopoietic stem cells (HSCs); however since Notch-deficient embryos die early in gestation, additional functions for Notch in embryonic HSC biology have not been described. We used two complementary genetic models to address this important bio...

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Autores principales: Gerhardt, Dawson M., Pajcini, Kostandin V., D’altri, Teresa, Tu, LiLi, Jain, Rajan, Xu, Lanwei, Chen, Michael J., Rentschler, Stacey, Shestova, Olga, Wertheim, Gerald B., Tobias, John W., Kluk, Michael, Wood, Antony W., Aster, Jon C., Gimotty, Phyllis A., Epstein, Jonathan A., Speck, Nancy, Bigas, Anna, Pear, Warren S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967047/
https://www.ncbi.nlm.nih.gov/pubmed/24637115
http://dx.doi.org/10.1101/gad.227496.113
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author Gerhardt, Dawson M.
Pajcini, Kostandin V.
D’altri, Teresa
Tu, LiLi
Jain, Rajan
Xu, Lanwei
Chen, Michael J.
Rentschler, Stacey
Shestova, Olga
Wertheim, Gerald B.
Tobias, John W.
Kluk, Michael
Wood, Antony W.
Aster, Jon C.
Gimotty, Phyllis A.
Epstein, Jonathan A.
Speck, Nancy
Bigas, Anna
Pear, Warren S.
author_facet Gerhardt, Dawson M.
Pajcini, Kostandin V.
D’altri, Teresa
Tu, LiLi
Jain, Rajan
Xu, Lanwei
Chen, Michael J.
Rentschler, Stacey
Shestova, Olga
Wertheim, Gerald B.
Tobias, John W.
Kluk, Michael
Wood, Antony W.
Aster, Jon C.
Gimotty, Phyllis A.
Epstein, Jonathan A.
Speck, Nancy
Bigas, Anna
Pear, Warren S.
author_sort Gerhardt, Dawson M.
collection PubMed
description Notch1 is required to generate the earliest embryonic hematopoietic stem cells (HSCs); however since Notch-deficient embryos die early in gestation, additional functions for Notch in embryonic HSC biology have not been described. We used two complementary genetic models to address this important biological question. Unlike Notch1-deficient mice, mice lacking the conserved Notch1 transcriptional activation domain (TAD) show attenuated Notch1 function in vivo and survive until late gestation, succumbing to multiple cardiac abnormalities. Notch1 TAD-deficient HSCs emerge and successfully migrate to the fetal liver but are decreased in frequency by embryonic day 14.5. In addition, TAD-deficient fetal liver HSCs fail to compete with wild-type HSCs in bone marrow transplant experiments. This phenotype is independently recapitulated by conditional knockout of Rbpj, a core Notch pathway component. In vitro analysis of Notch1 TAD-deficient cells shows that the Notch1 TAD is important to properly assemble the Notch1/Rbpj/Maml trimolecular transcription complex. Together, these studies reveal an essential role for the Notch1 TAD in fetal development and identify important cell-autonomous functions for Notch1 signaling in fetal HSC homeostasis.
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spelling pubmed-39670472014-09-15 The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells Gerhardt, Dawson M. Pajcini, Kostandin V. D’altri, Teresa Tu, LiLi Jain, Rajan Xu, Lanwei Chen, Michael J. Rentschler, Stacey Shestova, Olga Wertheim, Gerald B. Tobias, John W. Kluk, Michael Wood, Antony W. Aster, Jon C. Gimotty, Phyllis A. Epstein, Jonathan A. Speck, Nancy Bigas, Anna Pear, Warren S. Genes Dev Research Paper Notch1 is required to generate the earliest embryonic hematopoietic stem cells (HSCs); however since Notch-deficient embryos die early in gestation, additional functions for Notch in embryonic HSC biology have not been described. We used two complementary genetic models to address this important biological question. Unlike Notch1-deficient mice, mice lacking the conserved Notch1 transcriptional activation domain (TAD) show attenuated Notch1 function in vivo and survive until late gestation, succumbing to multiple cardiac abnormalities. Notch1 TAD-deficient HSCs emerge and successfully migrate to the fetal liver but are decreased in frequency by embryonic day 14.5. In addition, TAD-deficient fetal liver HSCs fail to compete with wild-type HSCs in bone marrow transplant experiments. This phenotype is independently recapitulated by conditional knockout of Rbpj, a core Notch pathway component. In vitro analysis of Notch1 TAD-deficient cells shows that the Notch1 TAD is important to properly assemble the Notch1/Rbpj/Maml trimolecular transcription complex. Together, these studies reveal an essential role for the Notch1 TAD in fetal development and identify important cell-autonomous functions for Notch1 signaling in fetal HSC homeostasis. Cold Spring Harbor Laboratory Press 2014-03-15 /pmc/articles/PMC3967047/ /pubmed/24637115 http://dx.doi.org/10.1101/gad.227496.113 Text en © 2014 Gerhardt et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Gerhardt, Dawson M.
Pajcini, Kostandin V.
D’altri, Teresa
Tu, LiLi
Jain, Rajan
Xu, Lanwei
Chen, Michael J.
Rentschler, Stacey
Shestova, Olga
Wertheim, Gerald B.
Tobias, John W.
Kluk, Michael
Wood, Antony W.
Aster, Jon C.
Gimotty, Phyllis A.
Epstein, Jonathan A.
Speck, Nancy
Bigas, Anna
Pear, Warren S.
The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells
title The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells
title_full The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells
title_fullStr The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells
title_full_unstemmed The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells
title_short The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells
title_sort notch1 transcriptional activation domain is required for development and reveals a novel role for notch1 signaling in fetal hematopoietic stem cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967047/
https://www.ncbi.nlm.nih.gov/pubmed/24637115
http://dx.doi.org/10.1101/gad.227496.113
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