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

Cheng Xu, Wei Bin Shen, E. Albert Reece, Hidetoshi Hasuwa, Christopher Harman, Sunjay Kaushal, Peixin Yang

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1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article numbereabf5089
JournalScience Advances
Volume7
Issue number27
DOIs
Publication statusPublished - 2021 Jun

ASJC Scopus subject areas

  • General

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