The PI's laboratory has recently uncovered the existence of a hitherto unknown family of genes present in organisms as diverse as mice, flies, and nematodes with a shared domain of homology also present in the classical mouse T locus. This domain has been named the T-box. The T-box region of the T locus product has been shown by other workers to have sequence- specific DNA binding activity. A role for the T locus product in regulating the proper development of a portion of the mesodermal lineage has been elucidated from results obtained by other investigators with mice, frogs, and zebrafish. In studies of the first three newly uncovered mouse members of the T-box family, unique patterns of temporal and spatial expression were demonstrated in the developing embryo. The working hypothesis is that the new T-box genes, like the prototypic al T locus, play critical roles in developmental signaling. The primary experimental objectives of this proposal and the companion application from Dr. Papaioannou are to identify the complete set of mouse T-box genes, investigate their evolutionary history, and determine the role that each plays in development. However, the overall goal is broader in scope and is aimed at a holistic view of the complete gene system, with an understanding of the structural and functional relationships that exist among the various T-box genes and, perhaps, the fundamental role that the T-box motif may have played in the evolution of developmental complexity. To accomplish this task will require investigations along the lines of genetics, molecular biology, evolution, and experimental embryology to be performed at Princeton and Columbia.
The specific aims of this proposal are; (1) Cloning nd characterization of the complete mouse T-box gene gamily. (2) Genetic analysis of mouse T-box genes to allow the identification and pursuit of candidate mouse mutations or human diseases caused by variant T- box alleles and the identification of gene clusters for further characterization through genomic analysis. T-box interactions with other genes will also be pursued through the mapping of modifier loci. (3) Understanding the evolution of the T-box gene family by cloning T-box homologs from a series of model organisms at different points in the metazoan phylogenetic tree. (40 Elucidating the functions of the T-box gene products through the identification of DNA binding sites and, ultimately, downstream target genes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD020275-16
Application #
2888902
Study Section
Special Emphasis Panel (ZRG2-MGN (Q1))
Program Officer
Moody, Sally Ann
Project Start
1984-09-30
Project End
2000-06-22
Budget Start
1999-04-01
Budget End
2000-06-22
Support Year
16
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Dow, H C; Kreibich, A S; Kaercher, K A et al. (2011) Genetic dissection of intermale aggressive behavior in BALB/cJ and A/J mice. Genes Brain Behav 10:57-68
Peirce, Jeremy L; Lu, Lu; Gu, Jing et al. (2004) A new set of BXD recombinant inbred lines from advanced intercross populations in mice. BMC Genet 5:7
Harrelson, Zachary; Kelly, Robert G; Goldin, Sarah N et al. (2004) Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development. Development 131:5041-52
Brodkin, Edward S; Hagemann, Andrea; Nemetski, Sondra Maureen et al. (2004) Social approach-avoidance behavior of inbred mouse strains towards DBA/2 mice. Brain Res 1002:151-7
Mahadevan, Navin R; Horton, Amy C; Gibson-Brown, Jeremy J (2004) Developmental expression of the amphioxus Tbx1/ 10 gene illuminates the evolution of vertebrate branchial arches and sclerotome. Dev Genes Evol 214:559-66
Horton, Amy C; Gibson-Brown, Jeremy J (2002) Evolution of developmental functions by the Eomesodermin, T-brain-1, Tbx21 subfamily of T-box genes: insights from amphioxus. J Exp Zool 294:112-21
Ruvinsky, Ilya; Chertkov, Olga; Borue, Xenia V et al. (2002) Genetics analysis of mouse mutations Abnormal feet and tail and rough coat, which cause developmental abnormalities and alopecia. Mamm Genome 13:675-9
Brodkin, Edward S; Goforth, Sarah A; Keene, Angela H et al. (2002) Identification of quantitative trait Loci that affect aggressive behavior in mice. J Neurosci 22:1165-70
Ahn, D G; Ruvinsky, I; Oates, A C et al. (2000) tbx20, a new vertebrate T-box gene expressed in the cranial motor neurons and developing cardiovascular structures in zebrafish. Mech Dev 95:253-8
Ruvinsky, I; Oates, A C; Silver, L M et al. (2000) The evolution of paired appendages in vertebrates: T-box genes in the zebrafish. Dev Genes Evol 210:82-91

Showing the most recent 10 out of 47 publications