We study the basis of mesoderm formation in the vertebrate embryo. As well as shedding light on fundamental developmental mechanisms, our work should assist efforts to direct stem cells down particular developmental pathways, and it might even allow us to make differentiated cells move backwards in developmental time, so that they can then be re-programmed as the experimenter desires.

Expression of Brachyury (blue stain) in a 9-day mouse embryo.

We use Xenopus species and the zebrafish, and have recently started work with mouse and human ES cells. In the embryo, one interest concerns the mechanism by which inducing factors exert long-range effects, and we are studying this by means of tagged forms of inducing factors such as activin and by using novel approaches to identify, in real time, the cells that respond to such signals. Like other members of the transforming growth factor type β family, activin exerts its effects by causing Smad proteins to form heteromeric complexes, and another aspect of our work has been to identify and characterise Smad-interacting proteins such as Smicl.

A second line of work involves elucidating the genetic regulatory networks that underlie mesoderm formation, and to this end we are carrying out ChIP-on-Chip and ChIP-Seq experiments, focussing on members of the T box family of proteins. The founder member of this family, Brachyury, is both necessary and sufficient for mesoderm formation. We shall go on to study gene function by use of antisense morpholino oligonucleotides, and we are also asking to what extent our results apply to ES cells and mammalian embryos.

Spread of labelled activin (green) through a responding tissue. The source of activin is to the left. At 2 hours (top) activin is predominantly extracellular; at 3.5 hours (bottom) much has become internalised.

Development of a new method of transgenesis should allow insertion of DNA sequences into defined insertion points in the genomes of Xenopus (above) as well as zebrafish and mouse embryos.

Plain English :
My laboratory is investigating how cells of the very early vertebrate embryo become different from each other, such that they go on to form specialised tissues such as muscle, skin, blood and bone. One way in which cells become different involves the establishment of a chemical gradient within a tissue; cells measure the local concentration of the chemical, and this tells them how to behave. We are studying how such gradients are set up, how cells measure the concentration of the chemical, and how this tells them what to do, such as activating a particular gene or moving to a different part of the embryo.

Selected publications:

• Saka Y, Hagemann A, Piepenburg O and Smith JC (2007) Nuclear accumulation of Smad complexes occurs only after the midblastula transition in Xenopus. Development 134, 4209-4218

• Eisen JS and Smith JC (2008) Controlling morpholino experiments: don’t stop making antisense. Development 135, 1735-1743.

• Sevilla LM, Rana AA, Watt FM, Smith JC (2008) KazrinA is required for axial elongation and epidermal integrity in Xenopus tropicalis. Dev Dyn 237, 1718-1725

• von Hofsten J, Elworthy S, Gilchrist M, Smith JC, Wardle FC and Ingham PW (2008) Prdm1- and Sox6-mediated transcriptional repression specifies muscle fibre type in the zebrafish embryo. EMBO Reports 9, 683-689

• Colas A, Cartry J, Buisson I, Umbhauer M, Smith JC and Riou JC (2008) Mix.1/2-dependent control of FGF availability during gastrulation is essential for pronephros development in Xenopus. Dev Biol 320, 351-365

Use of bimolecular fluorescence complementation reveals that signalling by nodal family members is strong near the margin of the embryo (bottom of image) and weak near the animal pole (top).

Dissociated animal pole cells expressing nuclear cyan fluorescent protein (blue) and Rab5 tagged with green fluorescent protein