Embryogenesis involves two distinct processes. On the one hand, cells must specialize, acquiring fates appropriate to their positions (differentiation);at the same time, they must physically construct the embryo through coordinated mechanical activity (morphogenesis). Recent studies in our laboratory demonstrate that the copper transporter 1 (Ctrl) protein functions as a key component that coordinates the differentiation and morphogenesis of multiple progenitor cell populations in the vertebrate embryo. In this application, we propose studies in embryos of the frog, Xenopus laevis, to define the mechanisms underlying the regulation of these processes by Ctrl. We will establish the distribution of Ctrl protein in the Xenopus embryo, (Aim 1);determine the signaling events through which Ctrl regulates embryonic cell fate (Aim 2);and determine the signaling events through which Ctrl regulates morphogenesis (Aim 3). It is anticipated that data from our studies will benefit workers from a number of biomedical disciplines. First, although copper imbalances underlie serious diseases in humans, many aspects of copper-related biology remain largely mysterious. Our research offers a rare opportunity to study the role of Ctrl, and of copper itself, in a well-defined, biologically relevant context that is representative of normal cellular function. Second, Ctrl has been shown to mediate the uptake of cisplatin, an effective cancer chemotherapy agent, as well as other platinum agents, in yeast, mouse, and human cells. These agents often elicit an encouraging initial response, followed by drug resistance during continued therapy. An understanding of the mechanisms of Ctrl function may provide vital clues as to how to offset resistance to cisplatin and other agents. Finally, we note that a large proportion of structural birth defects are likely to result from disturbances in morphogenesis. The proteins and the morphogenetic process that are the focus of this work play a crucial role in the movements of neurulation;thus, our studies may provide important insights into the origin of a particularly important class of birth defects, the neural tube malformations such as spina bifida.
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