Maternal Hyperglycemia Activates an ASK1–FoxO3a–Caspase 8 Pathway That Leads to Embryonic Neural Tube Defects

Sci. Signal., 27 August 2013
Vol. 6, Issue 290, p. ra74
DOI: 10.1126/scisignal.2004020

Maternal Hyperglycemia Activates an ASK1–FoxO3a–Caspase 8 Pathway That Leads to Embryonic Neural Tube Defects

  1. Peixin Yang1,2,*,
  2. Xuezheng Li1,
  3. Cheng Xu1,
  4. Richard L. Eckert2,
  5. E. Albert Reece1,2,
  6. Horst Ronald Zielke3, and
  7. Fang Wang1
  1. 1Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  2. 2Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  3. 3Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  1. *Corresponding author. E-mail: pyang{at}fpi.umaryland.edu

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.

Citation:

P. Yang, X. Li, C. Xu, R. L. Eckert, E. A. Reece, H. R. Zielke, and F. Wang, Maternal Hyperglycemia Activates an ASK1–FoxO3a–Caspase 8 Pathway That Leads to Embryonic Neural Tube Defects. Sci. Signal. 6, ra74 (2013).

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