Early temporal-specific responses and differential sensitivity to lithium and Wnt-3A exposure during heart development
Early temporal-specific responses and differential sensitivity to lithium and Wnt-3A exposure during heart development
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DOI：
10.1002/dvdy.20878
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发表时间：
2006-08-01
影响因子：
2.5
通讯作者：
Linask, Kersti K.
中科院分区：
文献类型：
--
作者：
Manisastry, Shyam M.;Han, Mingda;Linask, Kersti K.
信号分子 Wnt 和骨形态发生蛋白 (BMP) 家族的成员在心脏发育中非常重要。我们之前证明，β-连环蛋白是经典 Wnt 信号通路的关键下游中介，在前后进展中描绘了心室的背侧边界。我们假设该进展涉及典型的 Wnt 信号传导并反映了胚胎主要身体轴的发育。导致心肌细胞特异化的类似前后信号波涉及由前双侧区域的底层内胚层合成的 BMP-2 的诱导信号。任何破坏心脏区域内 Wnt 和 BMP 浓度正常平衡的分子都可能会影响早期心脏发育。锂模仿的典型 Wnt 信号传导步骤涉及糖原合酶激酶 3 β (GSK-3 β；Klein 和 Melton [1996] Proc. Natl. Acad. Sci. U.S.A. 93:8455-8459) 的失活。我们发现锂 Wnt-3A 和 GSK-3 beta 抑制剂 SB415286 会影响心脏规范阶段的早期心脏发育。我们证明，在鸡胚胎发育过程中的汉堡和汉密尔顿 (HH) 第 3 阶段，一次性接触锂或通过 BMP 的头蛋白抑制，心脏区域前中胚层中关键信号分子 Notch-1 和 Dkk-1 的正常表达模式发生改变。在 HH 第 3 阶段接触锂或 Wnt-3A 时，发育缺陷的严重程度最大，在 HH 第 4 阶段则降低。总而言之，我们的结果表明，在早期心脏发育过程中，对锂/Wnt-3A 暴露存在时间特异性反应和不同的敏感性。
Members of both Wnt and bone morphogenetic protein (BMP) families of signaling molecules are important in heart development. We previously demonstrated that beta-catenin, a key downstream intermediary of the canonical Wnt signaling pathway, delineates the dorsal boundary of the cardiac compartments in an anteroposterior progression. We hypothesized the progression involves canonical Wnt signaling and reflects development of the primary body axis of the embryo. A similar anteroposterior signaling wave leading to cardiac cell specification involves inductive signaling by BMP-2 synthesized by the underlying endoderm in anterior bilateral regions. Any molecule that disrupts the normal balance of Wnt and BMP concentrations within the heart field may be expected to affect early heart development. The canonical Wnt signaling step mimicked by lithium involves inactivation of glycogen synthase kinase-3 beta (GSK-3 beta; Klein and Melton [1996] Proc. Natl. Acad. Sci. U.S.A. 93:8455-8459). We show that lithium, Wnt-3A, and an inhibitor of GSK-3 beta, SB415286, affect early heart development at the cardiac specification stages. We demonstrate that normal expression patterns of key signaling molecules as Notch-1 and Dkk-1 are altered in the anterior mesoderm within the heart fields by a one-time exposure to lithium, or by noggin inhibition of BMP, at Hamburger and Hamilton (HH) stage 3 during chick embryonic development. The severity of developmental defects is greatest with exposure to lithium or Wnt-3A at HH stage 3 and decreases at HH stage 4. Taken together, our results demonstrate that there are temporal-specific responses and differential sensitivities to lithium/Wnt-3A exposure during early heart development.