1692-P: miR17 Overexpression or Deleting Its Target Gene Txnip Ameliorates Neural Tube Defect Formation in Diabetic Embryopathy

Abstract

microRNAs (miR) play important roles in the induction of diabetic embryopathy. Our previous studies have demonstrated that high glucose in vitro and maternal diabetes in vivo suppressed miR-17 expression. To determine whether miR17 down-regulation is involved in maternal diabetes-induced neural tube defects (NTDs) formation, we created a miR-17 transgenic (Tg) mouse line in which miR-17 specifically overexpresses in the developing neuroepithelium. miR-17 Tg male mice crossed with nondiabetic and diabetic (streptozotocin-induced type 1 diabetes) wild type (WT) female mice to generate WT and Tg embryos. Under nondiabetic conditions, there was no NTDs in both WT and Tg embryos. The NTD rate of WT embryos was 52.4% (22 out of 42 embryos) in diabetic pregnancy, whereas miR-17 overexpression in the neuroepithelium significantly reduced the NTD rate to 8.1% (3 out of 37 embryos). Txnip up-regulation is implicated in the pathogenesis of diabetes and diabetic complications. Txnip is a predicted miR-17 target genes, and miR-17 overexpression abolished maternal diabetes-increased Txnip expression. To investigate whether Txnip participates in the pathogenesis of diabetic embryopathy, the Txnip gene was deleted specifically in the neuroepithelium using the Cre-flox (f) approach by crossing Txnipf/w; nestin-cre male mice with nondiabetic or diabetic Txnipf/f female mice. Comparing to the NTD rate of 19.4% (7 out of 36 embryos) in WT embryos, embryos with conditional Txnip deletion had an NTD rate of 8.3% (1 out of 12 embryos). Our findings indicated that the miR-17-Txnip circuit is critically involved in the induction of diabetic embryopathy. Disclosure P. Yang: None. P. Yang: None. Funding American Diabetes Association (1-13-BS-220 to P.Y.); National Institutes of Health