Project Description. The long-term objective of this project is to understand the developmental roles of the T-box family of transcription factor genes. Mutation of Tbx4 results in early lethality due to failure of the allantois to fuse with the chorion and undergo vascular remodeling. We propose thatTbx4 is upstream of the Notch signaling pathway in vasculogenesis, controlling a cell fate decision between endothelial cells and pericytes, the supporting cells of blood vessels. In addition we have discovered a role for Tbx4 in hematopoiesis, as conditional mutants lacking Tbx4 after the establishment of the chorioallantoic placenta die of anemia. We will test the hypothesis that Tbx4 is essential for the differentiation and/or maintenance of hematopoietic stem cells (HSC) in the placental labyrinth. Tbx2, Tbx3 and Tbx20 homozygous mutants all die during gestation due to distinct defects in the heart. The expression domains of these genes are partially overlapping leading to the possibility of shared functions. We have uncovered a genetic interaction between Tbx2 and Tbx3 affecting postnatal viability that is likely due to genetic interaction in heart development. We will use mutations we have available to explore T-box gene interactions in the heart. The production of a conditional allele in Tbx3 will facilitate this endeavor and allow us to further investigate the role of Tbx3 in later development.
Specific Aim 1 : Test the hypothesis that Tbx4 is upstream of Notch signaling in vasculogenesis in the allantois.
Specific Aim 2 : Test the hypothesis that Tbx4 is essential for placental hematopoiesis and that placentally- derived hematopoietic stem cells seed the fetal liver.
Specific Aim 3 : Explore T-box gene interactions in heart development.
Specific Aim 4 : Produce a conditional allele of Tbx3 to examine the role of this gene in the heart and mammary gland. Relevance: T-box genes are central to many developmental processes. The discovery of placental hematopoiesis and the placental niche for HSC in the labyrinth point to a new site for fetal hematopoiesis with an important role for Tbx4. Our proposed studies have relevance to understanding stem cell biology of the hematpoietic system. Congenital heart defects (CHD) are the most common birth defects in humans and a leading cause of death in the first year of life. T-box transcription factors are critically involved in heart development and the mutations we have available provide a unique opportunity to unravel the molecular mechanisms underlying normal heart development and to identify overlapping functional roles of different T-box 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 #
5R37HD033082-15
Application #
8011368
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Coulombe, James N
Project Start
1996-02-01
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
15
Fiscal Year
2011
Total Cost
$391,340
Indirect Cost
Name
Columbia University (N.Y.)
Department
Genetics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Borok, Matthew J; Papaioannou, Virginia E; Sussel, Lori (2016) Unique functions of Gata4 in mouse liver induction and heart development. Dev Biol 410:213-22
Papaioannou, Virginia E (2016) Concepts of Cell Lineage in Mammalian Embryos. Curr Top Dev Biol 117:185-97
Washkowitz, Andrew J; Schall, Caroline; Zhang, Kun et al. (2015) Mga is essential for the survival of pluripotent cells during peri-implantation development. Development 142:31-40
Glaser, Anne; Arora, Ripla; Hoffmann, Sandra et al. (2014) Tbx4 interacts with the short stature homeobox gene Shox2 in limb development. Dev Dyn 243:629-39
Leitch, Harry G; Okamura, Daiji; Durcova-Hills, Gabriela et al. (2014) On the fate of primordial germ cells injected into early mouse embryos. Dev Biol 385:155-9
Papaioannou, Virginia E (2014) The T-box gene family: emerging roles in development, stem cells and cancer. Development 141:3819-33
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
Gavrilov, Svetlana; Harvey, Richard P; Papaioannou, Virginia E (2013) Lack of genetic interaction between Tbx20 and Tbx3 in early mouse heart development. PLoS One 8:e70149
Douglas, Nataki C; Papaioannou, Virginia E (2013) The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 18:143-7
Douglas, Nataki C; Arora, Ripla; Chen, Cayla Yiyu et al. (2013) Investigating the role of tbx4 in the female germline in mice. Biol Reprod 89:148

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