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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Development - 1 Study Section (DEV1)
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Haynes, Susan R
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Queens College
Biostatistics & Other Math Sci
Schools of Arts and Sciences
United States
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Grumolato, Luca; Liu, Guizhong; Haremaki, Tomomi et al. (2013) ?-Catenin-independent activation of TCF1/LEF1 in human hematopoietic tumor cells through interaction with ATF2 transcription factors. PLoS Genet 9:e1003603
Haremaki, Tomomi; Weinstein, Daniel C (2012) Eif4a3 is required for accurate splicing of the Xenopus laevis ryanodine receptor pre-mRNA. Dev Biol 372:103-10
Sridharan, Jyotsna; Haremaki, Tomomi; Jin, Ye et al. (2012) Xmab21l3 mediates dorsoventral patterning in Xenopus laevis. Mech Dev 129:136-46
Haremaki, Tomomi; Sridharan, Jyotsna; Dvora, Shira et al. (2010) Regulation of vertebrate embryogenesis by the exon junction complex core component Eif4a3. Dev Dyn 239:1977-87
Haremaki, Tomomi; Weinstein, Daniel C (2009) Xmc mediates Xctr1-independent morphogenesis in Xenopus laevis. Dev Dyn 238:2382-7
Haremaki, Tomomi; Fraser, Stuart T; Kuo, Yien-Ming et al. (2007) Vertebrate Ctr1 coordinates morphogenesis and progenitor cell fate and regulates embryonic stem cell differentiation. Proc Natl Acad Sci U S A 104:12029-34
Suri, Crystal; Haremaki, Tomomi; Weinstein, Daniel C (2005) Xema, a foxi-class gene expressed in the gastrula stage Xenopus ectoderm, is required for the suppression of mesendoderm. Development 132:2733-42
Suri, Crystal; Haremaki, Tomomi; Weinstein, Daniel C (2004) Inhibition of mesodermal fate by Xenopus HNF3beta/FoxA2. Dev Biol 265:90-104
Mohn, Deanna; Chen, Siming W; Dias, Dora Campos et al. (2003) Mouse Mix gene is activated early during differentiation of ES and F9 stem cells and induces endoderm in frog embryos. Dev Dyn 226:446-59
Hama, Joanne; Suri, Crystal; Haremaki, Tomomi et al. (2002) The molecular basis of Src kinase specificity during vertebrate mesoderm formation. J Biol Chem 277:19806-10

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