Martinez-Arias Lab

Department of Genetics, University of Cambridge

Jamie Trott

PhD student

jft33@cam.ac.uk
Department of Genetics,
Downing Street, Cambridge
CB2 3EH,England
Telephone: +44 1223 333965
Fax: +44 1223 333992

About me

I am interested in how cells integrate information about their state and the state of their environment and alter their behaviour accordingly, particularly during development. I did my Bachelor’s degree in Biochemistry at Imperial College London and my Master’s project at the EMBL in Heidelberg. In 2008 I moved to Cambridge and enrolled on the Wellcome Trust four-year PhD programme in Stem Cell Biology from which I was able to join the lab.

My Project – A novel role for Wnt signalling during mesoderm specification from Mouse Embryonic Stem Cells

ES cells are derived from early mammalian embryos and can be induced to differentiate into all of the different cell types of the adult organism, i.e. they are pluripotent (figure 1). The developmental plasticity of ES cells and their ability to propagate indefinitely in culture make them an ideal model system for studying lineage specification in vitro. However, there is evidence of heterogeneous gene expression within genetically homogeneous populations of mES cells and it is often observed that within such populations individual cells respond differently to differentiation signals.

Fig. 1Mouse Embryonic Stem Cells (mES cells) in culture
Please click on image to enlarge

Interestingly, several groups have shown that, within a population, dynamic expression of key developmental regulators generates interconvertible sub-populations of cells that are predisposed towards different lineages1,2,3,4 (figure 2). Such plasticity in cellular identity may be useful early in development when loss of a cell destined to form all, or a significant part of, a particular lineage would otherwise lead to loss of the embryo. However, at other times, such as gastrulation, cells must respond quickly and consistently to differentiation signals and it is likely that mechanisms exist to regulate heterogeneity during these periods.

Fig. 2 Expression of Nanog fluctuates in individual mES cells over time but Nanog levels across the population remain stable
Please click on image to enlarge

There is evidence that the Wnt signalling pathway acts to restrict gene expression heterogeneity across populations and ensure that cells respond consistently to signals5 (figure 3). Wnt signalling promotes pluripotency or mesendoderm differentiation of mES cells, depending on which other factors are present, and is involved in specification of several other lineages downstream of mesoderm6,7 (figure 4). I intend to use mesoderm differentiation from mES cells as a model system to test my hypothesis that the primary function of Wnt signalling during differentiation is to synchronise the responses of cells to differentiation signals.

Fig. 3 The Wnt signalling pathway
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Fig. 4 Signals acting on early lineage specificaiton events
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Expression level distributions for Wnt target genes will show whether Wnt homogenises expression levels across populations for a large number of genes (figure 5). Furthermore, if the positions of different cells within the distributions for different genes are known, I will be able to determine how Wnt affects the distribution of cells across different cell states. Expression time traces will show whether the distributions observed reflect the presence of different, stable populations or are the result of dynamic gene expression.

Fig. 5 Single cell and time lapse techniques for monitoring gene and protein expression in mES cells
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References

  1. Chambers I, Silva J, Colby D, Nichols J, Robertson M, Nijmeijer B, Vrana J, Jones K, Grotewold L, Smith A. 2007. Nanog safeguards pluripotency and mediates germ cell development. Nature 450:1230-1234.
  2. Yayoi Toyooka, Daisuke Shimosato, Kazuhiro Murakami, Kadue Takahashi1 and Hitoshi Niwa. 2008. Identification and characterization of subpopulations in undifferentiated ES cell culture. Development 135, 909-918.
  3. Canham MA, Sharov AA, Ko MSH, Brickman JM. 2010. Functional heterogeneity of embryonic stem cells revealed through translational amplification of an early endodermal transcript. PLoS Biol 8.
  4. Hayashi K, Lopes SM, Tang F and Surani MA. 2008. Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states. Cell Stem Cell 3, 391-401.
  5. Martinez-Arias A, Hayward P. 2006. Filtering transcriptional noise during development: concepts and mechanisms. Nature reviews vol 7.
  6. Kazuya Ogawa, Ryuichi Nishinakamura, Yuko Iwamatsu, Daisuke Shimosato and Hitoshi Niwa. 2006. Synergistic action of Wnt and LIF in maintaining pluripotency of mouse ES cells. Biochemical and Biophysical Research Communications Vol 3, Issue I, Pages 159-166.
  7. Charles E. Murry and Gordon Keller. 2008. Differentiation of Embryonic Stem Cells to Clinically Relevant Populations: Lessons from Embryonic Development. Cell 132, 661–680.

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