Apoptotic Mechanism of Maternal Diabetes-Induced Neural Tube Defects

University Of Maryland Baltimore, Baltimore MD

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Abstract

? DESCRIPTION (provided by applicant): Nearly 3 million American and 60 million worldwide women of reproductive age (18-44 years old) have diabetes, and this number is expected to double by 2030. Pregestational diabetes-induced neural tube defects (NTDs) remain a significant health problem. Activation of the Forkhead transcription factor 3a (FoxO3a) is essential for diabetes-induced neuroepithelial cell apoptosis and NTD formation. FoxO3a regulates microRNA (miRNA) expression, a group of small non-coding RNAs that silence gene expression. miRNAs are implicated in neural tube closure. Unraveling the mechanism underlying miRNA- mediated teratogenicity will add a new layer of posttranscriptional regulations in diabetic embryopathy, and provide a mechanistic basis for developing miRNAs as biomarkers for early NTD diagnosis and therapeutic interventions against diabetic embryopathy. We hypothesize that maternal diabetes-activated FoxO3a stimulates miR-200b expression and suppresses miR-322 though an interaction with histone deacetylase 1 (HADC1). miR-200b represses CITED2 expression that leads to endoplasmic reticulum (ER) stress, whereas diabetes-decreased miR-322 releases TRAF3 inhibition leading to neuroepithelial cell apoptosis. Either miR-200b deletion or miR-322 overexpression ameliorates NTD formation. MiR- 200b overexpression or miR-322 deletion exacerbates diabetic embryopathy. Aim 1 will determine the differential mechanisms underlying FoxO3a-induced miR-200b expression and miR-322 repression in diabetic embryopathy. We hypothesize that FoxO3a binds to the miR-200b promoter by stimulating its transcription, and interacts with HADC1 leading to miR-322 repression, and that the transactivation/chromatin remodeling domain of FoxO3a is required for both regulations. Aim 2 will investigate whether miR-200b mediates the teratogenicity of diabetes by down-regulating the neural tube closure essential factor CITED2 leading to ER stress and NTD formation. Our working hypothesis is that miR-200b transmits the teratogenicity of maternal diabetes by suppressing the neural tube closure essential gene, CITED2. Aim 3 will determine whether decreased miR-322 mediates the teratogenic effect of maternal diabetes by up-regulating the pro-apoptotic factor TRAF3. We hypothesize that miR-322 down-regulation contributes to the teratogenic effect of maternal diabetes by up-regulating TRAF3, and that miR-322 overexpression will ameliorate diabetes-induced NTDs, whereas deleting the miR-322 gene will enhance diabetic embryopathy.