Molecular effects of lithium exposure during mouse and chick gastrulation and subsequent valve dysmorphogenesis

作者：Jizhen Chen, Mingda Han, Shyam M. Manisastry, Patrizia Trotta, María Serrano, James C. Huhta, Kérsti K. Linask · 发表于：Birth Defects Research Part A Clinical and Molecular Teratology · 年份：2008 · DOI：10.1002/bdra.20448 · 被引用次数：25 · 研究领域：Congenital heart defects research、Wnt/β-catenin signaling in development and cancer、Tissue Engineering and Regenerative Medicine

BACKGROUND: Lithium (Li) has been associated with cardiac teratogenicity in the developing fetus. We took advantage of the association of therapeutic administration of Li with an increase in heart defects to gain insight into both normal and pathological heart and valve development with GSK-3 inhibition. The objective of this study was to define whether Li mimicry of canonical Wnt/beta-catenin signaling induces cardiac valve defects. METHODS: Li was administered by a single intraperitoneal injection to the pregnant mouse on embryonic day E6.75, much earlier than heretofore analyzed. On E15.5 developing heart defects were defined by Doppler ultrasound. The embryonic hearts were analyzed for changes in patterning of active canonical Wnt expression and nuclear factor of the activated T cells-c1 (NFATc1), both key regulators of valve development. Li-exposed chick embryos were used to define the early cell populations during gastrulation that are susceptible to GSK-3 inhibition and may relate to valve formation. RESULTS: Li exposure during gastrulation decreased the number of prechordal plate (PP) cells that reached the anterior intestinal portal, a region associated with valve development. Li decreased expression of Hex, an endoderm cardiac inducing molecule, normally also expressed by the PP cells, and of Sox 4 at the anterior intestinal portal and NFAT, critical factors in valvulogenesis. CONCLUSIONS: Cells existing already during gastrulation are associated with valve formatio...