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Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes

BACKGROUND: The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, invo...

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Autores principales: Rubio-Aliaga, Isabel, Przemeck, Gerhard K. H., Fuchs, Helmut, Gailus-Durner, Valérie, Adler, Thure, Hans, Wolfgang, Horsch, Marion, Rathkolb, Birgit, Rozman, Jan, Schrewe, Anja, Wagner, Sibylle, Hoelter, Sabine M., Becker, Lore, Klopstock, Thomas, Wurst, Wolfgang, Wolf, Eckhard, Klingenspor, Martin, Ivandic, Boris T., Busch, Dirk H., Beckers, Johannes, Hrabé de Angelis, Martin
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699037/
https://www.ncbi.nlm.nih.gov/pubmed/19562077
http://dx.doi.org/10.1371/journal.pone.0006054
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author Rubio-Aliaga, Isabel
Przemeck, Gerhard K. H.
Fuchs, Helmut
Gailus-Durner, Valérie
Adler, Thure
Hans, Wolfgang
Horsch, Marion
Rathkolb, Birgit
Rozman, Jan
Schrewe, Anja
Wagner, Sibylle
Hoelter, Sabine M.
Becker, Lore
Klopstock, Thomas
Wurst, Wolfgang
Wolf, Eckhard
Klingenspor, Martin
Ivandic, Boris T.
Busch, Dirk H.
Beckers, Johannes
Hrabé de Angelis, Martin
author_facet Rubio-Aliaga, Isabel
Przemeck, Gerhard K. H.
Fuchs, Helmut
Gailus-Durner, Valérie
Adler, Thure
Hans, Wolfgang
Horsch, Marion
Rathkolb, Birgit
Rozman, Jan
Schrewe, Anja
Wagner, Sibylle
Hoelter, Sabine M.
Becker, Lore
Klopstock, Thomas
Wurst, Wolfgang
Wolf, Eckhard
Klingenspor, Martin
Ivandic, Boris T.
Busch, Dirk H.
Beckers, Johannes
Hrabé de Angelis, Martin
author_sort Rubio-Aliaga, Isabel
collection PubMed
description BACKGROUND: The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1) is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1(C413Y)). Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized. CONCLUSIONS/SIGNIFICANCE: In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes.
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spelling pubmed-26990372009-06-29 Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes Rubio-Aliaga, Isabel Przemeck, Gerhard K. H. Fuchs, Helmut Gailus-Durner, Valérie Adler, Thure Hans, Wolfgang Horsch, Marion Rathkolb, Birgit Rozman, Jan Schrewe, Anja Wagner, Sibylle Hoelter, Sabine M. Becker, Lore Klopstock, Thomas Wurst, Wolfgang Wolf, Eckhard Klingenspor, Martin Ivandic, Boris T. Busch, Dirk H. Beckers, Johannes Hrabé de Angelis, Martin PLoS One Research Article BACKGROUND: The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1) is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1(C413Y)). Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized. CONCLUSIONS/SIGNIFICANCE: In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes. Public Library of Science 2009-06-29 /pmc/articles/PMC2699037/ /pubmed/19562077 http://dx.doi.org/10.1371/journal.pone.0006054 Text en Rubio-Aliaga et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Rubio-Aliaga, Isabel
Przemeck, Gerhard K. H.
Fuchs, Helmut
Gailus-Durner, Valérie
Adler, Thure
Hans, Wolfgang
Horsch, Marion
Rathkolb, Birgit
Rozman, Jan
Schrewe, Anja
Wagner, Sibylle
Hoelter, Sabine M.
Becker, Lore
Klopstock, Thomas
Wurst, Wolfgang
Wolf, Eckhard
Klingenspor, Martin
Ivandic, Boris T.
Busch, Dirk H.
Beckers, Johannes
Hrabé de Angelis, Martin
Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes
title Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes
title_full Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes
title_fullStr Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes
title_full_unstemmed Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes
title_short Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes
title_sort dll1 haploinsufficiency in adult mice leads to a complex phenotype affecting metabolic and immunological processes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699037/
https://www.ncbi.nlm.nih.gov/pubmed/19562077
http://dx.doi.org/10.1371/journal.pone.0006054
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