Maternal Diabetes Increases the Risk of Caudal Regression Caused by Retinoic Acid

Author:

Chan Billy W.H.1,Chan Kwok-siu1,Koide Tsuyoshi2,Yeung Sau-man1,Leung Maran B.W.1,Copp Andrew J.3,Loeken Mary R.4,Shiroishi Toshihiko2,Shum Alisa S.W.1

Affiliation:

1. Department of Anatomy, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China

2. Mammalian Genetics Laboratory, National Institute of Genetics, Mishima, Japan

3. Neural Development Unit, Institute of Child Health, University College London, London U.K.

4. Section on Cellular and Molecular Physiology and Department of Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts

Abstract

Maternal diabetes increases the risk of congenital malformations in the offspring of affected pregnancies. This increase arises from the teratogenic effect of the maternal diabetic milieu on the developing embryo, although the mechanism of this action is poorly understood. In the present study, we examined whether the vitamin A metabolite retinoic acid (RA), a common drug with well-known teratogenic properties, may interact with maternal diabetes to alter the incidence of congenital malformations in mice. Our results show that when treated with RA, embryos of diabetic mice are significantly more prone than embryos of nondiabetic mice to develop caudal regression, a defect that is highly associated with diabetic pregnancy in humans. By studying the vestigial tail (Wnt-3avt) mutant, we provide evidence that Wnt-3a, a gene that controls the development of the caudal region, is directly involved in the pathogenic pathway of RA-induced caudal regression. We further show that the molecular basis of the increased susceptibility of embryos of diabetic mice to RA involves enhanced downregulation of Wnt-3a expression. This positive interaction between RA and maternal diabetes may have implications for humans in suggesting increased susceptibility to environmental teratogens during diabetic pregnancy.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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