The long-term objectives of the proposed research are to characterize the members of a newly discovered, ancient family of embryonically-expressed mouse genes, the T-box genes, and to determine the functional roles they play in embryonic development. These genes share a conserved proton motif, the T-box, which co-localizes with the DNA binding activity of the prototypical T locus of the mouse, a locus which regulates mesoderm formation. Because of the evolutionary conservation between widely divergent species from nematode to mouse, these genes are likely to play a role in the development of all vertebrates. Our preliminary results with 6 newly discovered T-box genes reveal temporal and spatial expression patterns during embryogenesis, some unique and some overlapping that suggest interactive roles for these genes in different aspects of development. We will detail the expression of these genes and critically test their functional roles using mutational analysis. Although the research has specific goals that will be accomplished for the individual genes already identified, the overall objective is much broader in scope, and encompasses an attempt to understand the relationship between the various members of the gene families, and the basis of the evolutionary conservation of the shared motif. It is our belief, based our expression data and by analogy with other gene families with conserved, shared motifs such as Hox and Pax, that the T-box family of genes encodes a set of DNA binding proteins that each play a distinctive role in developmental signaling. our intention is to add new T-box genes to our investigation as they are identified and to concentrate efforts on individual genes or groups of related genes that appear most informative in elucidating developmental mechanisms. In order to accomplish this larger aim, this proposal is one component of a two-part Investigator-Initiated Interactive Research Project Grant (IRPG). Our collaborator, Dr. Lee Silver of Princeton University has been funded to pursue complementary work in his laboratory. The submission of this proposal as an IRPG reflects our shared objectives, complementary expertise and intention of continuing our existing collaborative arrangement to investigate this ancient family of mouse genes.
Specific Aim 1. Determine the expression pattern of mouse T-box genes, 1- 6, during embryogenesis, organogenesis and in the adult. We will use Northern blot analysis, in situ hybridization of tissue sections and whole mounts, and gene targeting constructs that include a marker gene driven by the endogenous promoter.
Specific Aim 2. To determine the function of T-box genes by creating null mutations using homologous recombination in embryonic stem cells. The phenotype of resulting mutant animals will be analyzed and the mutants will be mated together to study possible interactions between different genes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD033082-04
Application #
2872837
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Moody, Sally Ann
Project Start
1996-02-01
Project End
2001-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Genetics
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Burn, Sally F; Washkowitz, Andrew J; Gavrilov, Svetlana et al. (2018) Postimplantation Mga expression and embryonic lethality of two gene-trap alleles. Gene Expr Patterns 27:31-35
Levin, Heather I; Sullivan-Pyke, Chantae S; Papaioannou, Virginia E et al. (2017) Dynamic maternal and fetal Notch activity and expression in placentation. Placenta 55:5-12
Concepcion, Daniel; Papaioannou, Virginia E (2014) Nature and extent of left/right axis defects in T(Wis) /T(Wis) mutant mouse embryos. Dev Dyn 243:1046-53
Saadi, Irfan; Das, Pragnya; Zhao, Minglian et al. (2013) Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud-to-cap stage transition in tooth development. Development 140:2697-702
Lugani, Francesca; Arora, Ripla; Papeta, Natalia et al. (2013) A retrotransposon insertion in the 5' regulatory domain of Ptf1a results in ectopic gene expression and multiple congenital defects in Danforth's short tail mouse. PLoS Genet 9:e1003206
Douglas, Nataki C; Heng, Kathleen; Sauer, Mark V et al. (2012) Dynamic expression of Tbx2 subfamily genes in development of the mouse reproductive system. Dev Dyn 241:365-75
Papaioannou, V E; Behringer, R R (2012) Early embryonic lethality in genetically engineered mice: diagnosis and phenotypic analysis. Vet Pathol 49:64-70
Ballim, Reyna Deeya; Mendelsohn, Cathy; Papaioannou, Virginia E et al. (2012) The ulnar-mammary syndrome gene, Tbx3, is a direct target of the retinoic acid signaling pathway, which regulates its expression during mouse limb development. Mol Biol Cell 23:2362-72
Begum, Salma; Papaioannou, Virginia E (2011) Dynamic expression of Tbx2 and Tbx3 in developing mouse pancreas. Gene Expr Patterns 11:476-83
Naiche, L A; Arora, Ripla; Kania, Artur et al. (2011) Identity and fate of Tbx4-expressing cells reveal developmental cell fate decisions in the allantois, limb, and external genitalia. Dev Dyn 240:2290-300

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