Cyclic Nucleotides and the Response to Sonic Hedgehog

描述： Sonic Hedgehog是一种正常生活所必需的信号分子 中枢神经系统的发育。对Shh的反应是复杂的， 并且可以被像环胺这样的环境化合物改变。中的更改 Shh反应导致一种特定类型的胚胎畸形 以神经中线缺陷为特征，如全前脑畸形， 可在面部反映为眼球旋转或眼球过少。中的所有单元格类型 腹侧神经管的发育是Shh信号的结果，它是 很可能Shh反应中的微小变化对 腹侧细胞类型的形成。这反过来可能会导致先天性 神经缺陷。已经确定Shh的反应是 受反应细胞内环核苷酸浓度的影响。 增加cAMP浓度可减弱Shh反应，同时 CAMP依赖的激酶(PKA)激活Shh反应。这些作者 研究表明，增加cGMP浓度也会增强对 Shh，提出了Shh响应依赖于循环 反应细胞内的核苷酸浓度，以及cAMP和cGMP 对Shh的反应有相反的影响。有几种化合物存在于 环境可以改变细胞内环核苷酸的浓度， 要么通过激活GTP/ATP循环酶，产生循环的酶 核苷酸，或通过阻断磷酸二酯酶，降解环状的酶 核苷酸。据推测，环境中的化合物会改变 细胞的环核苷酸互补，改变这种细胞中的Shh反应， 导致胚胎畸形，从而导致出生缺陷。这一假说将 在鸡胚胎中使用Shh反应的敏感分析进行测试。它 将确定环境化合物是否会改变环状结构 细胞的核苷酸补体干扰正常的Shh信号 在体内发育神经管，或在体外神经外植体中发育。在人类身上， 暴露在将要测试的化合物中要么是自愿的，比如 Forsklin，或非自愿的，就像细菌肠毒素，但在任何一种情况下 对它们对早期胚胎可能产生的不良影响知之甚少，因此 作为出生缺陷的原因。

Description: The Sonic Hedgehog is a signaling molecule that is required for normal development of the central nervous system. The response to Shh is complex, and can be changed by environmental compounds like cyclopamine. Changes in the Shh response result in a specific type of embryo malformations characterized by defects of the neural midline, like holoprosencephaly, which can be reflected in the face as cyclopia or hypotelorism. All cell types in the ventral neural tube develop as a consequence of Shh signaling, and it is likely that small changes in the Shh response has subtle effects on the formation of ventral cell types. This in turn might result in congenital neurological defects. It has been determined that the Shh response is influenced by the cyclic nucleotide concentration within the responding cells. Increasing the camp concentration attenuates the Shh response, while loss of the camp dependent kinase (PKA) activates the Shh response. These authors showed that increasing the cGMP concentration also enhances the response to Shh, suggesting a model in which the Shh response is dependent on the cyclic nucleotide concentration within the responsive cells, and that camp and cGMP have opposite effects on the Shh response. Several compounds present in the environment can alter the intracellular cyclic nucleotide concentration, either by activating GTP/ATP cyclases, enzymes that generate cyclic nucleotides, or by blocking phosphodiesterases, enzymes that degrade cyclic nucleotides. It is hypothesized that environmental compounds that change the cyclic nucleotide complement of a cell, alter Shh response in such cells, resulting in embryo malformations and thus birth defects. The hypothesis will be tested using sensitive assays of the Shh response in the chick embryo. It will be determined if environmental compounds that change the cyclic nucleotide complement of a cell interfere with normal Shh signaling in the developing neural tube in vivo, or in neural explants in vitro. In humans, exposure to the compounds that will be tested is either voluntary, like forskolin, or involuntary, like bacterial enterotoxins, but in either case little is known about their possible adverse effects on early embryos and thus as a cause of birth defects.