Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1783716040462565376 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8245044 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT xucheng maternaldiabetesinducessenescenceandneuraltubedefectssensitivetothesenomorphicrapamycin AT shenweibin maternaldiabetesinducessenescenceandneuraltubedefectssensitivetothesenomorphicrapamycin AT reeceealbert maternaldiabetesinducessenescenceandneuraltubedefectssensitivetothesenomorphicrapamycin AT hasuwahidetoshi maternaldiabetesinducessenescenceandneuraltubedefectssensitivetothesenomorphicrapamycin AT harmanchristopher maternaldiabetesinducessenescenceandneuraltubedefectssensitivetothesenomorphicrapamycin AT kaushalsunjay maternaldiabetesinducessenescenceandneuraltubedefectssensitivetothesenomorphicrapamycin AT yangpeixin maternaldiabetesinducessenescenceandneuraltubedefectssensitivetothesenomorphicrapamycin |