Abstract

): The long-term goal of this project is to understand how the vertebrate embryo establishes its antero-posterior and dorso-ventral axes. In the previous grant period we established that the maternal cytoplasmic protein beta catenin plays a pivotal role in this process in the amphibian Xenopus laevis. In the absence of beta catenin, embryos gastrulate and form three germ layers but lack the dorsal derivatives (neural tube, notochord, somites, anterior endoderm) of those germ layers. We found that beta catenin was an essential component of a Xwnt signaling pathway, lying downstream of Xwnt and GSK-3 and upstream of the zygotic transcription factor siamois. This proposal is a continuation of these studies. Specifically, there are four questions that we aim to answer: 1. What is the role of the transcription factor XTcf3 in axis formation? 2. What is the role of Xnr3 in axis formation? 3. Is a head forming pathway downstream of XTcf3/beta catenin? 4. Is Xaxin the essential regulator of beta catenin function in axis formation? In recent years, it has become clear that the mechanisms governing differentiation of the early embryo are conserved across species, and used throughout development and in adult tissues to regulate patterning proliferation and regeneration. One example of this conservation is the Wnt signaling pathway, which is conserved in many of its components from sea urchin to mammals. Several lines of evidence implicate this pathway in cancer. Mutations of beta catenin have been found in a wide variety of tumor types (including cancer of the colon, duodenum, stomach, skin, breast and bladder), indicating a potent role for b-catenin as an oncogene. This study aims to increase our understanding of the regulation of beta catenin (Aim 4), the interactions of beta catenin (Aim 1) and the repertoire of direct target genes (Aim 2 and 4). This understanding is a prerequisite for the design of strategies for therapeutic interference with this pathway in anticancer treatment.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD033002-07
Application #
6636902
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Klein, Steven
Project Start
1995-05-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
7
Fiscal Year
2003
Total Cost
$266,400
Indirect Cost

  Institution

Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229

  Publications

Tadjuidje, Emmanuel; Kofron, Matthew; Mir, Adnan et al. (2016) Nodal signalling in Xenopus: the role of Xnr5 in left/right asymmetry and heart development. Open Biol 6:
White, Jody A; Heasman, Janet (2008) Maternal control of pattern formation in Xenopus laevis. J Exp Zool B Mol Dev Evol 310:73-84
Heasman, Janet (2006) Patterning the early Xenopus embryo. Development 133:1205-17
Liao, Guanghong; Tao, Qinghua; Kofron, Matthew et al. (2006) Jun NH2-terminal kinase (JNK) prevents nuclear beta-catenin accumulation and regulates axis formation in Xenopus embryos. Proc Natl Acad Sci U S A 103:16313-8
Heasman, Janet (2006) Maternal determinants of embryonic cell fate. Semin Cell Dev Biol 17:93-8
Sinner, Debora; Kirilenko, Pavel; Rankin, Scott et al. (2006) Global analysis of the transcriptional network controlling Xenopus endoderm formation. Development 133:1955-66
Birsoy, Bilge; Kofron, Matt; Schaible, Kyle et al. (2006) Vg 1 is an essential signaling molecule in Xenopus development. Development 133:15-20
Standley, Henrietta J; Destree, Olivier; Kofron, Matt et al. (2006) Maternal XTcf1 and XTcf4 have distinct roles in regulating Wnt target genes. Dev Biol 289:318-28
Tao, Qinghua; Yokota, Chika; Puck, Helbert et al. (2005) Maternal wnt11 activates the canonical wnt signaling pathway required for axis formation in Xenopus embryos. Cell 120:857-71
Yokota, Chika; Kofron, Matt; Zuck, Mike et al. (2003) A novel role for a nodal-related protein; Xnr3 regulates convergent extension movements via the FGF receptor. Development 130:2199-212

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