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Penny Hayward

Postdoc

pch34@cam.ac.uk
Department of Genetics,
Downing Street, Cambridge
CB2 3EH,England
Telephone: +44 1223 766742
Fax: +44 1223 333992

Cell fate decisions require the integration of various signalling inputs at the level of signal transduction and transcription. Wnt and Notch signalling are two important signalling systems that operate in concert in a variety of systems in vertebrates and invertebrates. Our work has established that the Notch receptor can modulate Wnt signalling and that its target is the activity and levels of Armadillo/β-catenin [12]. Further characterization of this role of Notch has shown that whilst Notch is able to suppress ectopic Wnt signalling induced by loss of GSK-3 function, the relationship between Notch and Axin (another member of the Armadillo/β-catenin destruction complex) is more complicated. We observe that there is synergy between Axin and Notch in the regulation of Armadillo/β-catenin [7].

These results combined with other observations collected within the lab over the years have led to the suggestion that Notch and Wnt signalling form an integrated module that plays a particular role during cell fate assignations [4,9]. While programmed interactions between signals and transcription factors determine developmental pathways and generate cell fates, Wnt/Notch signalling determines the efficiency of these processes i.e. they regulate the tempo and mode.

Using mouse embryonic stem cell (mES) as model systems, I am currently exploring the inputs of Wnt and Notch signalling into cell fate decisions and the mechanism by which these signal transduction pathways exert their influence.  Initially this work has focused on the characterization and influence of transcriptional noise in mES cells ([3] and see figure 1). This work utilizes flow cytometry amongst other techniques to analyse the influence of Wnt activity on the signalling and differentiation status of single cells.

Figure 1. In mES cells the levels of GFP/Nanog fluctuate within single cells over time, these fluctuations have functional consequences. A) TNGA Nanog reporter mES cells expressing GFP at different levels (R7, R8, and R9) were selected and FACS sorted as indicated. The isolated cells were subcultured for 2 days with samples taken every 24 hours and re analysed by flow cytometry. More than 28% and 38% of the Low Nanog (LN, R7) population transit to the High Nanog (HN) state in 24 hours and 48 hours, respectively, whereas less than 8% of R8 or R9 (High Nanog, HN) cells became GFP-negative during the same period of time. B) TNGA ES cells were sorted as LN and HN, based on their Nanog-reporter expression levels, and total RNA was purified. Semiquantitative RT-PCR analyses were performed to detect markers associated with both ES cell pluripotency and differentiation; the transcripts in each population and the cycle number are indicated in the figure. There are no significant differences between the subpopulations in the case of Oct4 expression, but only LN cells express detectable level of FGF5, a gene associated with differentiation. These observations suggested that the LN population is primed for differentiation.

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