Martinez-Arias Lab

Department of Genetics, University of Cambridge

Joaquín de Navascués

Postdoc

jd467@cam.ac.uk
Department of Genetics,
Downing Street, Cambridge
CB2 3EH,England
Telephone: +44 1223 766742
Fax: +44 1223 333992

Research interests

I am interested in the basic questions of Developmental Biology: growth, differentiation and morphogenesis. Cells in a developing organism must take at some time the decision of adopting a particular cell fate. Cells in tissues have to shape themselves into functional organs. While this happens, cellular mass has to build up through cell growth and division.
I have chosen to focus on the process of differentiation. I use the adult Drosophila midgut as a model [1,2] (Fig. 1A). This tissue is maintained by intestinal stem cells (ISCs) that have to decide whether to divide or differentiate, and then whether differentiate into an enterocyte or an enteroendocrine cell (Fig. 1B-D). What I like of this system is that it offers all the technical possibilities of Drosophila developmental genetics in a tissue that is in steady-state. For about two weeks, the cellular composition is fixed, and the operations that cells can engage into are the same. By contrast, classical systems such as the Drosophila embryo, imaginal discs or ovaries are in constant transformation, with new cell types or states or maturation being adopted every few hours. The questions one can pursue, however, remain the same. Regarding differentiation at least. Expanding the time window where the tissue does not evolve allows for a better understanding of the effects of cell signalling in the system.

Another appealing feature of this system is the potential insight one could contribute to our understanding of the stem cells of the mammalian intestine, with which the fruitfly midgut has many similarities.

My current aim is to study the the ISC division. This has been described to be asymmetric respect to the ISC fate [3], but there is only little information about how this happens. Also, there is the possibility that homeostasis is maintained stochastically through balanced symmetric divisions, as it has been shown for the murine interfollicular epidermis [4,5]. I am conducting both long-term lineage tracing experiments [6] and short-term twin-spot analysis [7] (Fig. 2) to discriminate between the two possibilities. This work is a collaboration with Prof. Benjamin Simons at the Cavendish Laboratory, who subjects my data to mathematical analysis. This way one can make powerful inferences that escape an analysis driven by intuition.

This is another side of this project that thrills me: I do believe that Cell and Molecular Biology has to move forward and embrace mathematics. To achieve deeper understanding (and leave the consideration of “soft science”) we have to engage in interdisciplinary work. My motivations for this are better explained in this lecture by Jeremy Gunawardena. I think that the sooner Biology undergraduates are provided a strong mathematical training, the better for our discipline (and our society).

Figure 1. A. Cartoon of the structure of the Drosophila intestine. ISCs have been described for the posterior midgut (shaded in gray). B. Confocal section showing the overall composition of the tissue. Large nuclei belong to the mature enterocytes. Small nuclei labelled with esg and the Notch reporter Gbe—SuH are of the enteroblasts, the differentiating daughters of the ISC. esg +ve, Gbe—SuH –ve cells are the ISCs. Small nuclei without specific label are the enteroendocrine cells and immature enterocytes. C. Confocal section showing the cell outlines (E-Cadherin), as well as esg +ve cells and enteroendocrine cells (Pros +ve). D. Cartoon depicting the cellular composition of the tissue and the different cell type markers.

Figure 2. Left: Cartoon illustrating the recombination process leading to the generation of syster lineages (i.e. labelled lineages where one daughter is traced with GFP and its sister cell with RFP) with the Twinspot Generator method [ref. 7]. Right: Application of the twinspot generator to the ISC division. One ISC has divided already, giving two single-coloured daughters, whereas another one has gone through the recombination process without dividing, hence the yellow (green+red) colour. esg is shown as undifferentiation marker.

Stepping stones

04/2008 – present: Research associate at the Alfonso Martínez-Arias' lab
06/2007 - 04/2008: Postdoctoral fellow at the Juan Modolell and Sonsoles Campuzano's lab
06/2007: PhD in Biology (Universidad Autónoma de Madrid)
Advisor: Juan Modolell
05/1999: Grade in Biology (Universidad Autónoma de Madrid)