Group leader: 

Val Wilson

Position: 

Lecturer in Developmental Biology

Contact: 

v [dot] wilson [at] ed [dot] ac [dot] uk

Aims
Our primary objective is to determine the nature of the progenitors for the mouse anteroposterior axis, and in particular answer the following questions:

1. Do these cells constitute a stem cell population, and what are their normal derivatives and differentiation potential?
2. What gene products define their identity as progenitors?
3. Can they be cultured in vitro?

Background
In mouse embryos, a number of lineage studies, including our own, point to the existence of a population of axial stem cells, located in the caudal end of the embryo in the primitive streak and tail bud. However, to date their properties remain unclear. We aim to determine the location and properties of these cells.

Approaches and progress

1. Lineage and potency of the axial progenitors
To address this question, two types of analysis are in progress in our laboratory. Firstly, to examine the normal derivatives of these cells, we are using an in vivo single cell labelling method to specifically identify descendants of cells in the primitive streak and tail bud. The results of this analysis will indicate whether they normally constitute multilineage or germ layer-restricted cells.

Figure 1. Labelled progeny of a single cell in the spinal cord, descending from axial progenitors.

A second approach is to determine the potency of these cells by grafting labelled putative stem cells to the primitive streak of embryos that are cultured in vitro. Through this analysis, we have identified a small area within the primitive streak and tail bud that contains the putative stem cells.

Figure 2. Putative axial progenitors and their descendents in the elongating anteroposteior axis.

2. Genetic pathways necessary for axial stem cell maintenance/differentiation
A number of factors (such as Brachyury, Wnt3A, and FGF family members) are expressed in the primitive streak and tail bud, and are also required for continued axial elongation. Their role in stem cell maintenance and differentiation remains unclear. We are investigating this in embryos by looking at the effect of gene misexpression on cell behaviour in the primitive streak. In a related approach, we are identifying novel genes that are required for axial elongation. Two such genes we identified in gene trap screens are Heparan sulphate 2-O-sulphotransferase and Jade-1. In collaboration with Ruth Arkell, MRC Mammalian Genetics Unit, Harwell, we are investigating the basis of novel chemically-induced short tail mutations.

3. In vitro culture of the axial stem cells
Data on the location and differentiation potential of axial stem cells, together with the elucidation of the factors necessary for their maintenance will facilitate prolonged in vitro culture of axial stem cells, and their directed differentiation to derivatives normally found in the embryo and adult.

Selected publications

• Tzouanacou E, Wegener A, Wymeersch FJ, Wilson V, Nicolas JF. 2009. Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis. Dev Cell 17(3):365-376. Press release.
• Cambray N and Wilson V. 2007. Two distinct sources for a population of maturing axial progenitors. Development 134:2829-2840.
• Bogani D, Warr N, Elms P, Davies J, Tymowska-Lalanne Z, Goldsworthy M, Cox R, Keays D, Flint J, Wilson VA, Nolan P, Arkel R. 2004. New semidominant mutations that affect mouse development. Genesis 40(2):109-117.
• Tzouanacou E, Tweedie S, Wilson V. 2003. Identification of Jade1, a gene encoding a PHD zinc finger protein, in a gene trap mutagenesis screen for genes involved in anteroposterior axis development. Mol Cell Biol. 23(23):8553-8562.
• Cambray N and Wilson VA. 2002. Axial progenitors with extensive potency are localised to the mouse chordoneural hinge. Development 129(20):4855-4866.
• Russ AP, Wattler S, Colledge WH, Aparicio SA, Carlton MB, Pearce JJ, Barton SC, Surani MA, Ryan K, Nehls MC, Wilson V, Evans MJ. 2000. Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature 404(6773):95-99.

Funding
Biotechnology and Biological Sciences Research Council (BBSRC)
European Commission FP6 Integrated Project EuroStemCell
Medical Research Council (MRC)
The Wellcome Trust
Stem Cell Sciences UK