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Functions of Huntingtin in Germ Layer Specification and Organogenesis

Huntington’s disease (HD) is a neurodegenerative disease caused by abnormal polyglutamine expansion in the huntingtin protein (Htt). Although both Htt and the HD pathogenic mutation (mHtt) are implicated in early developmental events, their individual involvement has not been adequately explored. In...

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Autores principales: Nguyen, Giang D., Molero, Aldrin E., Gokhan, Solen, Mehler, Mark F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742581/
https://www.ncbi.nlm.nih.gov/pubmed/23967334
http://dx.doi.org/10.1371/journal.pone.0072698
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author Nguyen, Giang D.
Molero, Aldrin E.
Gokhan, Solen
Mehler, Mark F.
author_facet Nguyen, Giang D.
Molero, Aldrin E.
Gokhan, Solen
Mehler, Mark F.
author_sort Nguyen, Giang D.
collection PubMed
description Huntington’s disease (HD) is a neurodegenerative disease caused by abnormal polyglutamine expansion in the huntingtin protein (Htt). Although both Htt and the HD pathogenic mutation (mHtt) are implicated in early developmental events, their individual involvement has not been adequately explored. In order to better define the developmental functions and pathological consequences of the normal and mutant proteins, respectively, we employed embryonic stem cell (ESC) expansion, differentiation and induction experiments using huntingtin knock-out (KO) and mutant huntingtin knock-in (Q111) mouse ESC lines. In KO ESCs, we observed impairments in the spontaneous specification and survival of ectodermal and mesodermal lineages during embryoid body formation and under inductive conditions using retinoic acid and Wnt3A, respectively. Ablation of BAX improves cell survival, but failed to correct defects in germ layer specification. In addition, we observed ensuing impairments in the specification and maturation of neural, hepatic, pancreatic and cardiomyocyte lineages. These developmental deficits occurred in concert with alterations in Notch, Hes1 and STAT3 signaling pathways. Moreover, in Q111 ESCs, we observed differential developmental stage-specific alterations in lineage specification and maturation. We also observed changes in Notch/STAT3 expression and activation. Our observations underscore essential roles of Htt in the specification of ectoderm, endoderm and mesoderm, in the specification of neural and non-neural organ-specific lineages, as well as cell survival during early embryogenesis. Remarkably, these developmental events are differentially deregulated by mHtt, raising the possibility that HD-associated early developmental impairments may contribute not only to region-specific neurodegeneration, but also to non-neural co-morbidities.
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spelling pubmed-37425812013-08-21 Functions of Huntingtin in Germ Layer Specification and Organogenesis Nguyen, Giang D. Molero, Aldrin E. Gokhan, Solen Mehler, Mark F. PLoS One Research Article Huntington’s disease (HD) is a neurodegenerative disease caused by abnormal polyglutamine expansion in the huntingtin protein (Htt). Although both Htt and the HD pathogenic mutation (mHtt) are implicated in early developmental events, their individual involvement has not been adequately explored. In order to better define the developmental functions and pathological consequences of the normal and mutant proteins, respectively, we employed embryonic stem cell (ESC) expansion, differentiation and induction experiments using huntingtin knock-out (KO) and mutant huntingtin knock-in (Q111) mouse ESC lines. In KO ESCs, we observed impairments in the spontaneous specification and survival of ectodermal and mesodermal lineages during embryoid body formation and under inductive conditions using retinoic acid and Wnt3A, respectively. Ablation of BAX improves cell survival, but failed to correct defects in germ layer specification. In addition, we observed ensuing impairments in the specification and maturation of neural, hepatic, pancreatic and cardiomyocyte lineages. These developmental deficits occurred in concert with alterations in Notch, Hes1 and STAT3 signaling pathways. Moreover, in Q111 ESCs, we observed differential developmental stage-specific alterations in lineage specification and maturation. We also observed changes in Notch/STAT3 expression and activation. Our observations underscore essential roles of Htt in the specification of ectoderm, endoderm and mesoderm, in the specification of neural and non-neural organ-specific lineages, as well as cell survival during early embryogenesis. Remarkably, these developmental events are differentially deregulated by mHtt, raising the possibility that HD-associated early developmental impairments may contribute not only to region-specific neurodegeneration, but also to non-neural co-morbidities. Public Library of Science 2013-08-13 /pmc/articles/PMC3742581/ /pubmed/23967334 http://dx.doi.org/10.1371/journal.pone.0072698 Text en © 2013 Nguyen 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
Nguyen, Giang D.
Molero, Aldrin E.
Gokhan, Solen
Mehler, Mark F.
Functions of Huntingtin in Germ Layer Specification and Organogenesis
title Functions of Huntingtin in Germ Layer Specification and Organogenesis
title_full Functions of Huntingtin in Germ Layer Specification and Organogenesis
title_fullStr Functions of Huntingtin in Germ Layer Specification and Organogenesis
title_full_unstemmed Functions of Huntingtin in Germ Layer Specification and Organogenesis
title_short Functions of Huntingtin in Germ Layer Specification and Organogenesis
title_sort functions of huntingtin in germ layer specification and organogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742581/
https://www.ncbi.nlm.nih.gov/pubmed/23967334
http://dx.doi.org/10.1371/journal.pone.0072698
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