Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin.
Cheng XuWei-Bin ShenE Albert ReeceHidetoshi HasuwaChristopher HarmanSunjay KaushalPeixin YangPublished in: Science advances (2021)
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.
Keyphrases
- cell cycle
- transcription factor
- dna damage
- endothelial cells
- type diabetes
- cell proliferation
- stress induced
- cardiovascular disease
- pregnancy outcomes
- poor prognosis
- high glucose
- pi k akt
- cell death
- long non coding rna
- risk factors
- adipose tissue
- gene expression
- drug delivery
- physical activity
- dna binding
- cancer therapy
- early onset
- copy number
- preterm birth
- genome wide identification