The vertebrate central nervous system develops from embryonic ectoderm in response to secreted factors produced by the dorsal signaling center known as the organizer. Although considerable progress has been made towards the identification of molecular products of the organizer, early molecular events leading to neural tissue development and neuronal differentiation are still poorly understood. Our preliminary data point to Frodo, a novel signaling protein, as one of the key regulators of neural tissue formation. Proposed studies will examine the function of Frodo in organizer formation and neural development. Signaling pathways that operate during neural development and involve Frodo and associated proteins will be defined. Molecular targets and regulators of Frodo will be characterized and the molecular mechanisms of its action will be studied in Xenopus embryos using gain- and loss-of-function approaches. A role for the homeodomain- interacting protein kinase (HIPK) as a possible mediator of Frodo function will be tested. These studies should provide insight into basic regulatory mechanisms, which operate during neural development and are likely to be misregulated in cancer. The knowledge of molecular pathways that involve HIPK and Frodo should allow the design of small molecules, which can modulate HIPK enzymatic activity, and will lead to the development of new anti-cancer therapies. As the same signaling mechanisms operate multiple times during early embryonic development in all vertebrate embryos, the regulation of these processes should prove useful in the prevention and correction of human birth defects.
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