The TGFß Superfamily A Tale of Gene Duplication and Divergence Billie J. Swalla...
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Transcript of The TGFß Superfamily A Tale of Gene Duplication and Divergence Billie J. Swalla...
The TGFß SuperfamilyA Tale of Gene Duplication
and Divergence
Billie J. [email protected]
October 16, 2006
Balemans & Van Hul (2002) Dev Biol. 250: 231-50.
Balemans & Van Hul (2002) Dev Biol. 250: 231-50.
TGFß Superfamily
OverachieversTGFß - 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
Gilbert 2003 Relationships Among Members of the TGF- Superfamily
Figure 6.21(2) The Smad Pathway Activated by TGF- Superfamily Ligands
Regulation of Chick Limb Apoptosis by BMP Signalling molecules
Q: How can the TGFß signaling pathway be modulated?
Just about every way imaginable!!
Herpin et al. ( 2004) Dev Comp Immunol. 28: 461-85.
TGFß Pathway Modulation
Herpin et al. ( 2004) Dev Comp Immunol. 28: 461-85.
Ligand Protein Structure
Herpin et al. ( 2004) Dev Comp Immunol. 28: 461-85.
Ligands that are Antagonists
Balemans & Van Hul (2002) Dev Biol. 250: 231-50.
BMP Antagonists and Human Disease
Balemans & Van Hul (2002) Dev Biol. 250: 231-50.
Balemans & Van Hul (2002) Dev Biol. 250: 231-50.
Receptors and Ligands
Balemans & Van Hul (2002) Dev Biol. 250: 231-50
Herpin et al. ( 2004) Dev Comp Immunol. 28: 461-85.
Receptor Protein Structure
Herpin et al. ( 2004) Dev Comp Immunol. 28: 461-85
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)
Herpin et al. ( 2004) Dev Comp Immunol. 28: 461-85
Smad Protein Structure
Miyazawa et al. ( 2002) Genes to Cells 7: 1191-1204
Miyazawa et al. ( 2002) Genes to Cells 7: 1191-1204
Miyazawa et al. ( 2002) Genes to Cells 7: 1191-1204
Miyazawa ( 2002) Genes to Cells 7: 1191-1204
Smad Protein Structure
Miyazawa ( 2002) Genes to Cells 7: 1191-1204
Miyazawa ( 2002) Genes to Cells 7: 1191-1204
Miyazawa ( 2002) Genes to Cells 7: 1191-1204
The Nodal pathway is highly conserved in vertebrates
Whitman, Dev Cell 2001 Nov;1(5):605-17Whitman, 1998
Nodal is Involved with Left-Right Asymmetry
Hamada et al., Nat Rev Genet 2002 Feb;3(2):103-13
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.
Swalla, 2001
coloniality
coloniality
Deuterostome Gastrulation
Chea and Swalla, 2005
Deuterostome Gastrulation
Solitary ascidians
have
bilateral
cleavage!
Tadpole larvae are asymmetric -
tail curling and the brain sensory organ
Lemaire P., Bertrand V., and Hudson C. 2002. Dev. Biol. 252: 151-169.
Ciona intestinalis
In situ hybridization of Nodal Is this expression causing morphological asymmetry?
A B C
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.
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.
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.
Solitary ascidians have bilateral cleavage!
Nodal is expressed asymmetrically before asymmetry is established.
Left-Right Asymmetry
Left Center
Left-Right Asymmetry Center Right
Siphons are asymmetric
Solitary ascidian
larvae
are
asymmetric!
Deuterostome Gastrulation
Swalla and Smith (2007)
Phil Tran R Soc B (in press)