Open AccessMaternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin
Author(s) -
Cheng Xu,
Wei Shen,
E. Albert Reece,
Hidetoshi Hasuwa,
Christopher Harman,
Sunjay Kaushal,
Peixin Yang
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abf5089
Subject(s) - neural tube , senescence , diabetes mellitus , biology , medicine , microbiology and biotechnology , neuroscience , endocrinology , embryo
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.