Advertisement

Fetal ethanol exposure activates protein kinase a and impairs Shh expression in prechordal mesendoderm cells in the pathogenesis of holoprosencephaly

Authors

  • Kazushi Aoto,

    1. Molecular Neuropathology Group, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198
    Current affiliation:
    1. Stowers Institute for Medical Research, 1000 E. 50th St., Kansas City, MO 64110
    Search for more papers by this author
  • Yayoi Shikata,

    1. Molecular Neuropathology Group, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198
    Search for more papers by this author
  • Daisuke Higashiyama,

    1. Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
    Search for more papers by this author
  • Kohei Shiota,

    1. Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
    Search for more papers by this author
  • Jun Motoyama

    Corresponding author
    1. Molecular Neuropathology Group, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198
    • Molecular Neuropathology Group, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
    Search for more papers by this author

Abstract

BACKGROUND:

In humans, fetal ethanol exposure can cause holoprosencephaly (HPE), one of the most common birth defects that is characterized by brain, facial, and oral abnormalities. However, the pathogenesis of HPE is not clear. In the present study, we investigated the teratogenic mechanism of ethanol-induced brain and facial malformations in mice.

METHODS:

Pregnant C57BL/6J mice were administered ethanol on E7 and facial and brain malformations were characterized on E10.5. We examined the effect of fetal ethanol exposure on Shh expression and activation of protein kinase A (PKA) because mutations in the human Shh gene are the most frequent cause of autosomal-dominant inherited HPE and PKA is a potent endogenous antagonist of Shh signaling.

RESULTS:

Fetal ethanol exposure on E7 induced severe midline defects characteristic of HPE. Ethanol exposure impaired Shh expression and induced excessive apoptosis only along the anterior edge of the prechordal mesendoderm (PME). In addition, ethanol activated PKA in anterior PME cells. Pretreatment of embryos with antioxidants, such as vitamins C or E, prevented the development of ethanol-induced HPE.

CONCLUSIONS:

Shh expression in PME cells is involved in the pathogenesis of ethanol-induced HPE. Ethanol may impair Shh expression indirectly by activating PKA. The inhibition of excessive apoptosis in PME cells by antioxidants implies that oxidative stress may underlie the teratogenic actions of ethanol. Thus, antioxidant treatment may be a simple preventative measure that could reduce the incidence of HPE following fetal ethanol exposure. Birth Defects Research (Part A), 2008. © 2008 Wiley-Liss, Inc.

Ancillary