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

Abstract

Neural tube defects (NTDs) are the second most common structural birth defects. Senescence, a state of permanent cell cyle arrest, only occurs after neural tube closure. Maternal diabetes-induced NTDs, severe diabetic complications leading to infant mortality or lifelong morbidity, 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 deleting the transcription factor Foxo3a, the miR-200c gene, the cell cycle inhibitors p21 or p27, or by transgenic expression of the dominant-negative FoxO3a mutant or by 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 neruoepithelium senescence, and provide a mechanistic basis for targeting premature senescence and NTDs using senomorphs.