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  • (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. Note that the T-box binds its target DNA (teal and blue) as a homodimer. (Lower) Human TBX5 and X. laevis Xbra T-box sequences are aligned. The Gly80Arg (R) and Arg237Gln (Q) missense mutations are located in the T-box sequence. A vertical line indicates identical sequences in Xbra and TBX5, two dots indicate functionally related residues, and one dot denotes nonconserved residues.

NIH NIH Presentation Transcript

  • T Box Genes, TBX 5 and Clues about Heart and Limb Development
    • T Box Genes-Background
    • TBX5-Positional Cloning
    • TBX5 Mutations and Cell Biology
    • Heart and Limb Development
    • NHGRI/NIH November 23, 2009
    • David 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
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  • 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-Background
    • TBX5-Positional Cloning
    • TBX5 Mutations and Cell Biology
    • Heart and Limb Development
    • NHGRI/NIH November 23, 2009
    • David R. Bachinsky, Ph.D.
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  • T Box Genes, TBX 5 and Clues about Heart and Limb Development
    • T Box Genes-Background
    • TBX5-Positional Cloning
    • TBX5 Mutations and Cell Biology
    • Heart and Limb Development
    • NHGRI/NIH November 23, 2009
    • David R. Bachinsky, Ph.D.
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  • 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
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  • (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-Background
    • TBX5-Positional Cloning
    • TBX5 Mutations and Cell Biology
    • Heart and Limb Development
    • NHGRI/NIH November 23, 2009
    • David R. Bachinsky, Ph.D.
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  • 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.html http://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 You
    • NHGRI/NIH November 23, 2009
    • David R. Bachinsky, Ph.D.
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  • Srivastava, D. Cell. 2006 Sep 22;126(6):1037-48 .
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  • 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
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  • Moskowitz etal. Cell (2007) 129:1365
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  • Moody, Principles of Developmental Genetics, AP Press, 2007.
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  • 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.
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  • 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)
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