The broad goal of this research proposal is to understand the molecular and cellular basis of signaling mechanisms underlying mesoderm induction in the vertebrate embryo. In Xenopus, mesoderm induction involves at least two intracellular signaling pathways, downstream of the FGF and TGF-beta receptors. Overexpression of components of either pathway causes ectopic formation of mesoderm, while interruption of signaling through either pathway inhibits mesoderm formation in vivo. The two signaling pathways may interact, as FGF signaling is required for TGF-beta pathway function; it has been proposed that FGF signaling is involved in the competence of early tissue to form mesoderm in response to a TGF-beta inducing cue. Laloo, a novel member of the Src-related gene family, plays a critical role in FGF-mediated mesoderm induction. This application focuses on the FGF-Laloo pathway: the proposed studies aim to characterize the molecular interactions underlying signaling by Laloo, using a combination of embryological and biochemical approaches. Experiments are designed to 1) elucidate the mechanisms by which the FGF receptor regulates the activity of Laloo, 2) determine the specificity of signaling by the Src-like kinases, and 3) characterize the role of extracellular matrix components in Laloo activation. These experiments should provide a detailed understanding of the mechanisms by which Laloo mediates mesoderm induction by FGF, and will extend, considerably, the understanding of Src kinase function in this fundamental step in vertebrate development. These experiments will also lay the groundwork for future studies designed to explore the means by which this pathway and others coordinate the range, timing, and extent of mesoderm induction during vertebrate embryogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061671-02
Application #
6520292
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Greenberg, Judith H
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$279,675
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
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

Showing the most recent 10 out of 11 publications