Drb Nih Talk Jan 2009

1. TBX5: Clues about Heart-Limb Development Holt-Oram Syndrome Mapping and Cloning TBX5 TBX5 Mutations and Cell Biology T Box Genes Organ and Limb Development NIDCR/NIH January 15, 2009 David R. Bachinsky, Ph.D.

3. TBX5 mutant mouse on bottom. Photo: Malcolm Logan

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

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

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

31. Fan, C. et al. J. Biol. Chem. 2003;278:8780-8785 Immunostaining of NIH-3T3 cells expressing human TBX5

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

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

35. T Box History 1927-Brachyury or T gene identified, lethal in homozygotes and a short tail in heterozygotes. 1995-first mammalian gene positionally cloned DNA binding domain-T box domain identified 18 members of gene family, 5 subfamilies

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

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

43. Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Fig. 3. The heart of Drosophila

44. Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Fig. 4. Schematic of transcriptional networks involved in mammalian heart development

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

46. Moskowitz etal. Cell (2007) 129:1365

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

48. Logan, M. Development 2003;130:6401-6410 (A) Representation of the prospective limb territories in a stage 15 chick embryo

49. Logan, M. Development 2003;130:6401-6410 Representation of the signals required for forelimb initiation and subsequent limb outgrowth in the mouse

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

51. TBX Genes (Products) and Associated Human Diseases 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)

54. Collaborators Jonathan and Christine (Kricket) Seidman Craig Basson Robert Lin Johann Soults Tatiana Levi Raju Kucherlapati Cynthia Morton

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

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

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

95. Hasson, P. et al. Development 2007;134:85-92 Model depicting two phases of limb development

103. Bruneau, Nature (2008) 451:943

104. Bruneau, Nature (2008) 451:943

105. Bruneau, Nature (2008) 451:943

106. Bruneau, Nature (2008) 451:943

Drb Nih Talk Jan 2009

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Drb Nih Talk Jan 2009