Molecular Signalling Pathways and Cellular Stress in Diabetic Embryopathy

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Pregestational diabetes-induced neural tube defects (NTDs) remain a significant health problem. Kinase signaling-induced cellular stress is considered to be a causal event in NTD formation. However, the cause of stress-altered developmental programming relative to neurulation remains elusive. We found that both maternal type 1 and type 2 diabetes induce premature senescence in the developing neural tube. We also observed that deleting either the p21 gene or the p27 gene, the senescence mediators, ameliorates diabetes-induced NTD formation. Additionally, deletion of the microRNA-200c/141 (miR-200c/141) locus, which induces senescence in cultured cells, abolishes the increase of senescence mediators through the downregulation of the transcriptional repressor ZEB1 and ZEB2. Diabetes-increased miR-200c/141 expression is abrogated by superoxide dismutase 1 overexpression. Thus, we hypothesize that maternal diabetes induces premature senescence in proliferative cells of the developing neuroepithelium leading to failed neural fold fusion through up-regulation of miR-200c/141 by the oxidative stress-activated ASK1-FoxO3a pathway. miR-200c/141 up-regulates senescence mediators p21 and p27 through suppression of transcription repressors, ZEB1 and ZEB2. These senescence mediators arrest cell cycle progress of proliferative apical neuroepithelial cells leading to NTDs. Aim 1 will determine the characteristics of premature senescence during neurulation and whether diabetes-induced oxidative stress is the cause of senescence in diabetic pregnancy. We hypothesize that diabetes induces p21 expression specifically in the developing neuroepithelium leading to premature senescence in inhibiting neural fold fusion, and diabetes-induced oxidative stress is responsible for the induction of senescence in proliferative apical neuroepithelial cells. Aim 2 will investigate whether the oxidative stress-activated ASK1-FoxO3a pathway increases miR-200c/miR-141 that mediates maternal diabetes-induced premature senescence and NTDs. We will examine that diabetes induces miR-200c/141 through the ASK1-FoxO3a pathway, and that miR-200c/141 deletion suppresses p21 expression through liberating ZEB1/2 expression leading to inhibition of premature senescence and NTDs. Aim 3 will determine whether p21 and p27 induce cell cycle arrest in apical neuroepithelial cells leading to premature senescence and NTD formation in diabetic pregnancy. We will test the hypothesis that both p21 and p27 mediate cell cycle arrest and premature senescence in diabetic embryopathy, and that deletion of p21 and/or p27 ameliorates senescence and NTDs. We will continue to explore the role of key kinase signaling in senescence, a new developmental program, in diabetic embryopathy and to reveal how miRNAs participates in maternal diabetes-induced senescence.