1. The TGFß Superfamily A Tale of Gene Duplication and Divergence Billie J. Swalla bjswalla@u.washington.edu October 16, 2006

2. Balemans & Van Hul (2002) Dev Biol. 250: 231-50.

4. TGFß Superfamily Overachievers TGFß - Transforming Growth Factor Beta - was found to be mutated in cells that were cancerous BMPs - Bone Morphogenetic Protein - substance that could promote bone diferentiation if added to cultured cells. Nodal - Expressed in the mouse node - necessary for mesoderm formation in vertebrates and left-right asymmetry in deuterostomes Activin - Necessary for D-V axis in vertebrates

5. Gilbert 2003 Relationships Among Members of the TGF-  Superfamily

6. Figure 6.21(2) The Smad Pathway Activated by TGF-  Superfamily Ligands

7. Regulation of Chick Limb Apoptosis by BMP Signalling molecules

8. Q: How can the TGFß signaling pathway be modulated? Just about every way imaginable!!

9. Herpin et al. ( 2004) Dev Comp Immunol. 28: 461- 85. TGFß Pathway Modulation

10. Herpin et al. ( 2004) Dev Comp Immunol. 28: 461- 85. Ligand Protein Structure

11. Herpin et al. ( 2004) Dev Comp Immunol. 28: 461- 85.

13. Ligands that are Antagonists Balemans & Van Hul (2002) Dev Biol. 250: 231-50.

14. BMP Antagonists and Human Disease Balemans & Van Hul (2002) Dev Biol. 250: 231-50.

16. Receptors and Ligands Balemans & Van Hul (2002) Dev Biol. 250: 231-50

17. Herpin et al. ( 2004) Dev Comp Immunol. 28: 461- 85. Receptor Protein Structure

18. Herpin et al. ( 2004) Dev Comp Immunol. 28: 461-85

19. Miyazawa ( 2002) Genes to Cells 7: 1191- 1204 All About Smads R-Smads (Receptor-regulated Smads) e.g. Smad2 and Smad3 Activated by activin, nodal and TGFß (Alk4,5,7) Co-Smads (Common partner Smads) R-Smad and Co-Smads interact with co-activators and co-repressors and transcription factors I-Smads (Inhibitory Smads) Associate with type I receptors and prevent the activation of R-Smads (Smad 6 inhibits Smad 4)

20. Herpin et al. ( 2004) Dev Comp Immunol. 28: 461-85 Smad Protein Structure

21. Miyazawa et al. ( 2002) Genes to Cells 7: 1191-1204

24. Miyazawa ( 2002) Genes to Cells 7: 1191- 1204 Smad Protein Structure

25. Miyazawa ( 2002) Genes to Cells 7: 1191-1204

28. The Nodal pathway is highly conserved in vertebrates Whitman, Dev Cell 2001 Nov;1(5):605-17 Whitman, 1998

29. Nodal is Involved with Left-Right Asymmetry Hamada et al., Nat Rev Genet 2002 Feb;3(2):103-13

30. Bilateral Expression of nodal is correlated with situs inversus in vertebrates Xenopus tadpoles Chick embryos Campione et al., 1999 Levin et al., 1995 Development 126, 1225-1234. Cell 82(5), 803-814.

31. Swalla, 2001 coloniality

32. Deuterostome Gastrulation Chea and Swalla, 2005

33. Deuterostome Gastrulation

34. Solitary ascidians have bilateral cleavage! Tadpole larvae are asymmetric - tail curling and the brain sensory organ

35. Lemaire P., Bertrand V., and Hudson C. 2002. Dev. Biol. 252: 151-169. Ciona intestinalis

36. In situ hybridization of Nodal Is this expression causing morphological asymmetry? A BC During gastrulation, Nodal is bilaterally expressed in one trunk lateral cell and three ectodermal cells. At the initial tailbud stage, Nodal is asymmetrically expressed on the left side exclusively in the epidermal cells.

37. Anr-1 expression in the gastrula stage Expression of Anr-1 at the gastrula stage in Molgula oculata. Fate map of the ascidian gastrula. Anr-1 is expressed in the mesenchyme precursor cells and the trunk lateral cells From Nishida, 1987.

38. Asymmetric expression of Nodal is conserved between ascidians and vertebrates Expression of Anr-1 and Nodal in ascidian and mouse embryos. Asymmetric expression of Nodal and Nodal -related genes is conserved between the urochordate and vertebrate lineages. Mouse image from Melloy et al, 1998.

39. Solitary ascidians have bilateral cleavage!

40. Nodal is expressed asymmetrically before asymmetry is established.

41. Left-Right Asymmetry Left Center

42. Left-Right Asymmetry Center Right

43. Siphons are asymmetric

44. Solitary ascidian larvae are asymmetric!

45. Deuterostome Gastrulation Swalla and Smith (2007) Phil Tran R Soc B (in press)