title: Maternal hyperglycemia activates an ASK1-FoxO3a-caspase 8 pathway that leads to embryonic neural tube defects.
abstract: Neural tube defects result from failure to completely close neural tubes during development. Maternal diabetes is a substantial risk factor for neural tube defects, and available evidence suggests that the mechanism that links hyperglycemia to neural tube defects involves oxidative stress and apoptosis. We demonstrated that maternal hyperglycemia correlated with activation of the apoptosis signal-regulating kinase 1 (ASK1) in the developing neural tube, and Ask1 gene deletion was associated with reduced neuroepithelial cell apoptosis and development of neural tube defects. ASK1 activation stimulated the activity of the transcription factor FoxO3a, which increased the abundance of the apoptosis-promoting adaptor protein TRADD, leading to activation of caspase 8. Hyperglycemia-induced apoptosis and the development of neural tube defects were reduced with genetic ablation of either FoxO3a or Casp8 or inhibition of ASK1 by thioredoxin. Examination of human neural tissues affected by neural tube defects revealed increased activation or abundance of ASK1, FoxO3a, TRADD, and caspase 8. Thus, activation of an ASK1-FoxO3a-TRADD-caspase 8 pathway participates in the development of neural tube defects, which could be prevented by inhibiting intermediates in this cascade.
authors: Department of Obstetrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA. pyang@fpi.umaryland.edu
authors: Peixin
authors: P
authors: Yang
authors: Xuezheng
authors: X
authors: Li
authors: Cheng
authors: C
authors: Xu
authors: Richard L
authors: RL
authors: Eckert
authors: E Albert
authors: EA
authors: Reece
authors: Horst Ronald
authors: HR
authors: Zielke
authors: Fang
authors: F
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D015151:Immunoblotting; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009436:Neural Tube Defects / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D053199:TNF Receptor-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D053199:TNF Receptor-Associated Death Domain Protein; D013879:Thioredoxins; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D053181:Caspase 8; D005947:Glucose
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