Modulation of Dishevelled and Vangl2 by all-trans-retinoic acid in the developing mouse central nervous system and its relationship to teratogenesis.
The response to exposure to all-trans-retinoic acid (RA) during embryogenesis varies from physiologic to severe teratogenic effects and is dependent upon the dose and the stage of development in all species. Vangl2 and Dishevelled genes play key roles in establishing planar cell polarity and regulating convergent extension movements during the neurula period. The effects of RA-mediated teratogenesis might be due to its misregulation of Vangl2 and Dishevelled genes. The aim of this study is to monitor the modulation of Vangl2 and Dishevelled in Kunming mouse embryos following maternal treatment with a single oral dose of 30 mg/(kg body weight) of RA during the neurula period. Exposure of 7.75 d embryos to RA induced characteristic morphological changes. The most obvious external effect was the failure of neural tube closure in the midbrain and forebrain regions in 10 d embryos, resulting in exencephaly in later embryos. RA treatment also led to a pronounced decrease of Vangl2 mRNA at 4 and 18 h and a pronounced increase at 66 h after maternal treatment, as detected by reverse transcription-polymerase chain reaction. Western blot analysis showed a marked decrease of Vangl2 protein at 18 and 42 h and a marked increase at 66 and 90 h after maternal treatment. Dishevelled1/2/3 mRNA was significantly down-regulated at 4 and 18 h and up-regulated at 42 h in the fetus after RA treatment, except for an up-regulation of Dishevelled3 at 66 h. The Dishevelled2 mRNA and its protein matched each other. These results hinted that Vangl2 and Dishevelled genes might take part in RA teratogenesis of mouse embryos.
Zhang
Yanping
Y
Department of Histology and Embryology, Medical College of Shandong University, Jinan 250012, China.
Liu
Kai
K
Gao
Yingmao
Y
Li
Shaoling
S
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002490:Central Nervous System / Q000196:embryology* / Q000378:metabolism; D000072261:Dishevelled Proteins; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000009:adverse effects / Q000502:physiology*