the tgfß superfamily a tale of gene duplication and divergence billie j. swalla...

The TGFß SuperfamilyA Tale of Gene Duplication

and Divergence

Billie J. Swallabjswalla@u.washington.edu

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)