T Box Genes, TBX 5 and Clues about Heart and Limb

Development

T Box Genes-BackgroundTBX5-Positional Cloning TBX5 Mutations and Cell Biology Heart and Limb Development

NHGRI/NIH November 23, 2009David R. Bachinsky, Ph.D.

T Box History

1927-Brachyury (short tail), T gene.Nadine Dobrovolskaïa-Zavadskaïa-Pasteur Institute

http://www.informatics.jax.orggreenbook/figures/figure8-2.shtml

TBX dimers bound to DNA.. Muller and Herrmann, Nature (1997) 389:884

Horton etal. Dev Genes Evol (2008) 218:613

TBX Genes (Products) and Human Disease

• T gene Spinal Bifida• TBX1 DiGeorge Syndrome (CATCH 22)• TBX3 Ulnar Mammary Syndrome (UMS)• TBX4 Small patella• TBX5 Holt-Oram Syndrome (HOS, Heart-Hand)• TBX19 POMC Deficiency (TPIT)• TBX20 Heart Defects (septal, conduction defects)• TBX15 Acromegaloid facial appearance (candidate)• TBX21 Asthma (TBET)• TBX22 Cleft palate with ankyloglossia (X linked)

T Box Genes, TBX 5 and Clues about Heart and Limb

Development

T Box Genes-BackgroundTBX5-Positional Cloning TBX5 Mutations and Cell Biology Heart and Limb Development

NHGRI/NIH November 23, 2009David R. Bachinsky, Ph.D.

T Box Genes, TBX 5 and Clues about Heart and Limb

Development

T Box Genes-BackgroundTBX5-Positional Cloning TBX5 Mutations and Cell Biology Heart and Limb Development

NHGRI/NIH November 23, 2009David R. Bachinsky, Ph.D.

Fan, C. et al. J. Biol. Chem. 2003;278:8780-8785

Immunostaining of NIH-3T3 cells expressing human TBX5

Camarata etal. J Cell Bio (2006) 174:339

Kulisz and Simon, Mol Cell Bio (2008) 28:1553

(Upper) Three-dimensional structure of the X. laevis Xbra T-box bound to a 24-nt DNA duplex indicating the location of residues Gly-80 (red) and Arg-237 (yellow) mutated in the missense

mutations Gly80Arg, Arg237Gln, and Arg237Trp

Basson C. T. et.al. PNAS 1999;96:2919-2924

©1999 by The National Academy of Sciences

T Box Genes, TBX 5 and Clues about Heart and Limb

Development

T Box Genes-BackgroundTBX5-Positional Cloning TBX5 Mutations and Cell Biology Heart and Limb Development

NHGRI/NIH November 23, 2009David R. Bachinsky, Ph.D.

TBX5 mutant mouse on bottom. Photo: Malcolm Logan

Plageman, T. F. et al. J. Biol. Chem. 2004;279:19026-19034

The T-box binding consensus sequences of the ANF promoter are required for regulation by Tbx5 and Tbx20

Srivastava, D. Cell. 2006 Sep 22;126(6):1037-48.

http://www.nature.com/nature/journal/v459/n7247/abs/nature08039.htmlhttp://www.nature.com/nature/journal/v461/n7260/abs/nature08324.html

T Box Genes, TBX 5 and Clues about Heart and Limb

Development

Conclusions

1 Holt-Oram Syndrome caused by haploinsufficiency of TBX5

2 TBX5 master regulator gene in heart septation (wall formation) and forelimb development (radial)

3 TBX5 involved in: Splicing mRNA, chamber formation, and induction of beating cardiomyocytes

Collaborators

• Jonathan and Christine (Cricket) Seidman• Craig Basson• Robert Lin• Johann Soults• Tatiana Levi• Benoit Bruneau• Raju Kucherlapati• Cynthia Morton

T Box Genes, TBX5 and Clues about Heart and Limb

Development

Thank YouNHGRI/NIH November 23, 2009David R. Bachinsky, Ph.D.

Srivastava, D. Cell. 2006 Sep 22;126(6):1037-48.

http://www.nature.com/nature/journal/v459/n7247/full/459654a.html

TBX 3/5-forelimbs (ulnar/radius) and

TBX2/4-hindlimbs (tibia/fibia)

Photo : Malcolm Logan

Moskowitz etal. Cell (2007) 129:1365

Moody, Principles of Developmental Genetics, AP Press, 2007.

Published by AAAS

E. N. Olson Science 313, 1922 -1927 (2006)

Fig. 3. The heart of Drosophila

Horton etal. Dev Genes Evol (2008) 218:613

Chick embryos 4 Day Gestation, in situ hybridization. The cells expressing Tbx5 will form a wing; those expressing Tbx4 will form a leg. Tbx4 and Tbx5 code for related gene regulatory proteins, which are thought to dictate which type of limb develops. H. Ohuchi et al., Development (1998)125:51–60

Logan, M. Development 2003;130:6401-6410

(A) Representation of the prospective limb territories in a stage 15 chick embryo

Rodriguez-Esteban etal, Nature (1999) 398:814

Horton etal., Dev Genes Evol (2008) 218:613.

http://www.nature.com/nature/journal/v459/n7247/abs/nature08039.html

Bruneau. Nature, 451:943 (2008)

Horton etal., Dev Genes Evol (2008) 218:613.

Bruneau. Nature, 451:943 (2008)

Bruneau. Nature, 451:94(2008)

Bruneau. Nature, 451:943 (2008)