Cyclic Nucleotides and the Response to Sonic Hedgehog

点击翻译按钮获取中文摘要

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.