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Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin

Neural tube defects (NTDs) are the second most common structural birth defect. Senescence, a state of permanent cell cycle arrest, occurs only after neural tube closure. Maternal diabetes–induced NTDs are severe diabetic complications that lead to infant mortality or lifelong morbidity and may be li...

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Autores principales: Xu, Cheng, Shen, Wei-Bin, Reece, E. Albert, Hasuwa, Hidetoshi, Harman, Christopher, Kaushal, Sunjay, Yang, Peixin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245044/
https://www.ncbi.nlm.nih.gov/pubmed/34193422
http://dx.doi.org/10.1126/sciadv.abf5089
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author Xu, Cheng
Shen, Wei-Bin
Reece, E. Albert
Hasuwa, Hidetoshi
Harman, Christopher
Kaushal, Sunjay
Yang, Peixin
author_facet Xu, Cheng
Shen, Wei-Bin
Reece, E. Albert
Hasuwa, Hidetoshi
Harman, Christopher
Kaushal, Sunjay
Yang, Peixin
author_sort Xu, Cheng
collection PubMed
description Neural tube defects (NTDs) are the second most common structural birth defect. Senescence, a state of permanent cell cycle arrest, occurs only after neural tube closure. Maternal diabetes–induced NTDs are severe diabetic complications that lead to infant mortality or lifelong morbidity and may be linked to premature senescence. Here, we report that premature senescence occurs in the mouse neuroepithelium and disrupts neurulation, leading to NTDs in diabetic pregnancy. Premature senescence and NTDs were abolished by knockout of the transcription factor Foxo3a, the miR-200c gene, and the cell cycle inhibitors p21 and p27; transgenic expression of the dominant-negative FoxO3a mutant; or the senomorphic rapamycin. Double transgenic expression of p21 and p27 mimicked maternal diabetes in inducing premature neuroepithelium senescence and NTDs. These findings integrate transcription- and epigenome-regulated miRNAs and cell cycle regulators in premature neuroepithelium senescence and provide a mechanistic basis for targeting premature senescence and NTDs using senomorphics.
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spelling pubmed-82450442021-07-13 Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin Xu, Cheng Shen, Wei-Bin Reece, E. Albert Hasuwa, Hidetoshi Harman, Christopher Kaushal, Sunjay Yang, Peixin Sci Adv Research Articles Neural tube defects (NTDs) are the second most common structural birth defect. Senescence, a state of permanent cell cycle arrest, occurs only after neural tube closure. Maternal diabetes–induced NTDs are severe diabetic complications that lead to infant mortality or lifelong morbidity and may be linked to premature senescence. Here, we report that premature senescence occurs in the mouse neuroepithelium and disrupts neurulation, leading to NTDs in diabetic pregnancy. Premature senescence and NTDs were abolished by knockout of the transcription factor Foxo3a, the miR-200c gene, and the cell cycle inhibitors p21 and p27; transgenic expression of the dominant-negative FoxO3a mutant; or the senomorphic rapamycin. Double transgenic expression of p21 and p27 mimicked maternal diabetes in inducing premature neuroepithelium senescence and NTDs. These findings integrate transcription- and epigenome-regulated miRNAs and cell cycle regulators in premature neuroepithelium senescence and provide a mechanistic basis for targeting premature senescence and NTDs using senomorphics. American Association for the Advancement of Science 2021-06-30 /pmc/articles/PMC8245044/ /pubmed/34193422 http://dx.doi.org/10.1126/sciadv.abf5089 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Xu, Cheng
Shen, Wei-Bin
Reece, E. Albert
Hasuwa, Hidetoshi
Harman, Christopher
Kaushal, Sunjay
Yang, Peixin
Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin
title Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin
title_full Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin
title_fullStr Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin
title_full_unstemmed Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin
title_short Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin
title_sort maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245044/
https://www.ncbi.nlm.nih.gov/pubmed/34193422
http://dx.doi.org/10.1126/sciadv.abf5089
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