Drb Nih Talk Jan 2009

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  • Drb Nih Talk Jan 2009

    1. 1. TBX5: Clues about Heart-Limb Development <ul><li>Holt-Oram Syndrome </li></ul><ul><li>Mapping and Cloning TBX5 </li></ul><ul><li>TBX5 Mutations and Cell Biology </li></ul><ul><li>T Box Genes </li></ul><ul><li>Organ and Limb Development </li></ul><ul><li>NIDCR/NIH January 15, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    2. 3. TBX5 mutant mouse on bottom. Photo: Malcolm Logan
    3. 5. TBX dimers bound to DNA.. Muller and Herrmann, Nature (1997) 389:884
    4. 7. TBX5: Clues about Heart-Limb Development <ul><li>Holt-Oram Syndrome </li></ul><ul><li>Mapping and Cloning TBX5 </li></ul><ul><li>TBX5 Mutations and Cell Biology </li></ul><ul><li>T Box Genes </li></ul><ul><li>Organ and Limb Development </li></ul><ul><li>NIDCR/NIH January 15, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    5. 9. Moody, Principles of Developmental Genetics, AP Press, 2007.
    6. 11. TBX5: Clues about Heart-Limb Development <ul><li>Holt-Oram Syndrome </li></ul><ul><li>Mapping and Cloning TBX5 </li></ul><ul><li>TBX5 Mutations and Cell Biology </li></ul><ul><li>T Box Genes </li></ul><ul><li>Organ and Limb Development </li></ul><ul><li>NIDCR/NIH January 15, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    7. 22. TBX5: Clues about Heart-Limb Development <ul><li>Holt-Oram Syndrome </li></ul><ul><li>Mapping and Cloning TBX5 </li></ul><ul><li>TBX5 Mutations and Cell Biology </li></ul><ul><li>T Box Genes </li></ul><ul><li>Organ and Limb Development </li></ul><ul><li>NIDCR/NIH January 15, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    8. 29. (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
    9. 31. Fan, C. et al. J. Biol. Chem. 2003;278:8780-8785 Immunostaining of NIH-3T3 cells expressing human TBX5
    10. 32. Kulisz and Simon, Mol Cell Bio (2008) 28:1553
    11. 33. Camarata etal. J Cell Bio (2006) 174:339
    12. 34. TBX5: Clues about Heart-Limb Development <ul><li>Holt-Oram Syndrome </li></ul><ul><li>Mapping and Cloning TBX5 </li></ul><ul><li>TBX5 Mutations and Cell Biology </li></ul><ul><li>T Box Genes </li></ul><ul><li>Organ and Limb Development </li></ul><ul><li>NIDCR/NIH January 15, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    13. 35. T Box History <ul><li>1927-Brachyury or T gene identified, lethal in homozygotes and a short tail in heterozygotes. </li></ul><ul><li>1995-first mammalian gene positionally cloned </li></ul><ul><li>DNA binding domain-T box domain identified </li></ul><ul><li>18 members of gene family, 5 subfamilies </li></ul>
    14. 36. Horton etal. Dev Genes Evol (2008) 218:613
    15. 39. Horton etal. Dev Genes Evol (2008) 218:613
    16. 40. TBX5: Clues about Heart-Limb Development <ul><li>Holt-Oram Syndrome </li></ul><ul><li>Mapping and Cloning TBX5 </li></ul><ul><li>TBX5 Mutations and Cell Biology </li></ul><ul><li>T Box Genes </li></ul><ul><li>Organ and Limb Development </li></ul><ul><li>NIDCR/NIH January 15, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    17. 43. Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Fig. 3. The heart of Drosophila
    18. 44. Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Fig. 4. Schematic of transcriptional networks involved in mammalian heart development
    19. 45. 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
    20. 46. Moskowitz etal. Cell (2007) 129:1365
    21. 47. 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
    22. 48. Logan, M. Development 2003;130:6401-6410 (A) Representation of the prospective limb territories in a stage 15 chick embryo
    23. 49. Logan, M. Development 2003;130:6401-6410 Representation of the signals required for forelimb initiation and subsequent limb outgrowth in the mouse
    24. 50. Rodriguez-Esteban etal, Nature (1999) 398:814
    25. 51. TBX Genes (Products) and Associated Human Diseases <ul><li>T gene Spinal Bifida </li></ul><ul><li>TBX1 DiGeorge Syndrome (CATCH 22) </li></ul><ul><li>TBX3 Ulnar Mammary Syndrome (UMS) </li></ul><ul><li>TBX4 Small patella </li></ul><ul><li>TBX5 Holt-Oram Syndrome (HOS, Heart-Hand) </li></ul><ul><li>TBX19 POMC Deficiency (TPIT) </li></ul><ul><li>TBX20 Heart Defects (septal, conduction defects) </li></ul><ul><li>TBX15 Acromegaloid facial appearance (candidate) </li></ul><ul><li>TBX21 Asthma (TBET) </li></ul><ul><li>TBX22 Cleft palate with ankyloglossia (X linked) </li></ul>
    26. 54. Collaborators <ul><li>Jonathan and Christine (Kricket) Seidman </li></ul><ul><li>Craig Basson </li></ul><ul><li>Robert Lin </li></ul><ul><li>Johann Soults </li></ul><ul><li>Tatiana Levi </li></ul><ul><li>Raju Kucherlapati </li></ul><ul><li>Cynthia Morton </li></ul>
    27. 56. Horton etal., Dev Genes Evol (2008) 218:613.
    28. 57. Horton etal., Dev Genes Evol (2008) 218:613.
    29. 59. TBX5: Clues about Heart-Limb Development <ul><li>Holt-Oram Syndrome </li></ul><ul><li>Mapping and Cloning TBX5 </li></ul><ul><li>TBX5 Mutations and Cell Biology </li></ul><ul><li>T Box Genes </li></ul><ul><li>Organ and Limb Development </li></ul><ul><li>NIDCR/NIH January 15, 2009 </li></ul><ul><li>David R. Bachinsky, Ph.D. </li></ul>
    30. 61. Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Fig. 2. Simplified structures of different types of hearts, showing schematic diagrams of hearts and directions of blood flow
    31. 95. Hasson, P. et al. Development 2007;134:85-92 Model depicting two phases of limb development
    32. 96. Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Fig. 2. Simplified structures of different types of hearts, showing schematic diagrams of hearts and directions of blood flow
    33. 97. Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Fig. 2. Simplified structures of different types of hearts, showing schematic diagrams of hearts and directions of blood flow
    34. 98. GRN subcircuits used in both Drosophila and sea urchin development Davidson E. H., Levine M. S. PNAS 2008;105:20063-20066 ©2008 by National Academy of Sciences
    35. 103. Bruneau, Nature (2008) 451:943
    36. 104. Bruneau, Nature (2008) 451:943
    37. 105. Bruneau, Nature (2008) 451:943
    38. 106. Bruneau, Nature (2008) 451:943

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