Details

Autor(en) / Beteiligte

• CHAN, Billy W. H
• CHAN, Kwok-Siu
• KOIDE, Tsuyoshi
• YEUNG, Sau-Man
• LEUNG, Maran B. W
• COPP, Andrew J
• LOEKEN, Mary R
• SHIROISHI, Toshihiko
• SHUM, Alisa S. W

Titel

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

Ist Teil von

• Diabetes (New York, N.Y.), 2002-09, Vol.51 (9), p.2811-2816

Ort / Verlag

Alexandria, VA: American Diabetes Association

Erscheinungsjahr

2002

Quelle

MEDLINE

Beschreibungen/Notizen

• Maternal Diabetes Increases the Risk of Caudal Regression Caused by Retinoic Acid Billy W.H. Chan 1 , Kwok-siu Chan 1 , Tsuyoshi Koide 2 , Sau-man Yeung 1 , Maran B.W. Leung 1 , Andrew J. Copp 3 , Mary R. Loeken 4 , Toshihiko Shiroishi 2 and Alisa S.W. Shum 1 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-3a vt ) 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. Footnotes Address correspondence and reprint requests to Alisa S.W. Shum, Department of Anatomy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong. E-mail: alisa-shum{at}cuhk.edu.hk . Received for publication 18 October 2001 and accepted in revised form 22 May 2002. dpc, days postcoitus; RA, retinoic acid; RAR, retinoic acid receptor. DIABETES