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Early One‐time Lithium Exposure In Utero Affects Tricuspid Valve Morphogenesis in the Mouse Embryo
Author(s) -
Chen Jizhen,
Manisastry S.M.,
Han Mingda,
Linask Kersti K
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb2-c
Subject(s) - wnt signaling pathway , lithium (medication) , embryo , morphogenesis , medicine , embryogenesis , embryonic stem cell , biology , microbiology and biotechnology , chemistry , endocrinology , andrology , signal transduction , genetics , gene
Lithium (Li) therapeutically used to treat bipolar disorder results in a high incidence of birth defects, specifically Ebstein's Anomaly that is characterized by tricuspid valve defects. Lithium mimics canonical Wnt / β‐catenin signaling by its inhibition of glycogen synthase kinase‐3β. Little is known about how lithium leads to valve defects. We used TOPGAL mice exposed to lithium to identify the connection between the Wnt pathway and valve development. The TOPGAL transgene consists of a ß‐galactosidase gene driven by a T cell factor (TCF), ß‐catenin responsive promoter, to detect canonical Wnt activity by X‐gal staining. Pregnant female TOPGal mice received a single intraperitoneal (IP) injection (100ul of 6.5 mg/ml) of Li on ED 6.75, and control embryos, the same concentration of NaCl. Embryos exposed to Li in utero showed fewer X‐gal expressing cells in the endocardial cushion (EC) on ED11.5 than the control embryos. On ED 15.5 X‐gal expressing cells are more widely spread in the EC of Li‐exposed embryos than in control hearts where the cells were more organized in appearance and closely associated. On ED 15.5 delamination of the valve leaflet in the Li‐exposed embryo does not occur. This suggests that normal signaling between the cells in this region has been disrupted. These results indicate that an IP injection of lithium on ED 6.75 results in abnormal EC formation and subsequently a failure of the tricuspid valve septal leaflet to delaminate. In conclusion early, acute, embryonic lithium exposure affects valve morphogenesis to result in Ebstein's Anomaly. Supported by NIH grant HL67306 to KKL