Cell polarity is essential both for cell function and for several key developmental processes, such as cell migration, axis determination and asymmetric cell division, whereas loss of polarity is a critical step in the formation of tumours.We use Drosophila and mammalian tissue culture cells to analyse how polarity is established, taking a combination of cell-biological, genetic and molecular approaches.

Much of our work focuses on how epithelial cells become polarised along their apical-basal axis, using the follicle cells as a typical secretory epithelium and the adult midgut as model absorptive epithelium.We have recently discovered that the tumour suppressor, LKB1, and the energy sensor, AMPK, are required for epithelial polarity under conditions of energetic stress, revealing the existence of a distinct low energy polarity pathway.We have identified several other components of this pathway in Drosophila and mammals, all of which have been implicated in cancer. We are currently analysing the functions of these factors and are performing genetic screens for new genes required for epithelial polarity under either high or low energy conditions.

In parallel, we are examining how the Drosophila oocyte is polarised, since the localisation of bicoid and mRNAs to opposite ends of this very large cell defines the anterior-posterior axis of the embryo.We are using proteomic and biochemical approaches to elucidate how conserved polarity proteins regulate the organisation of the microtubule cytoskeleton in the oocyte, and we are investigating the mechanisms of mRNA transport by making time-lapse films of moving mRNA particles in wildtype and mutant oocytes. In addition, we are performing genetic screens for mutants that affect the localisations of bicoid and oskar mRNAs, and are analysing the novel polarity and mRNA localisation factors that these identify.

A model showing the polarity factors that mark different cortical domains in epithelial cells and the inhibitory interactions between them.

Starvation-dependent tumour formation. Removal of the AMP-dependent protein kinase from clones of follicle cells (marked by the absence of GFP; green) causes the cells to lose their polarity and over-proliferate, resulting in small tumours. This phenotype is only observed under starvation conditions.

A stage 10 egg chamber expressing a marker for the microtubule minus ends fused to Cherry fluorescent protein (red), counterstained for DNA (blue). The minus ends of the microtubules are anchored to the anterior cortex of the oocyte and direct the localisation of bicoid mRNA.

Plain English:
Most cells are polarised, with one end being different from the other. For example, a motor neuron receives inputs into dendrites and transmits these signals down an axon for many centimetres to the other end of the cell, where chemical messengers are released to stimulate muscle contraction. Since polarised cells like neurons perform different functions at each end of the cell, they need to localise the proteins that perform these functions, and this is often achieved by localising the mRNAs from which the proteins are translated. One of the best examples of this is provided by the egg of the fruitfly, Drosophila, where the anterior localisation of bicoid mRNA determines where the head will form, and the posterior localisation of oskar mRNA defines where the abdomen develops. Because it is easy to make mutants in Drosophila and the egg is a very large cell, we are using this system to investigate the conserved molecular mechanisms that polarise cells and target mRNAs to the right place. Although this is basic research, it is relevant to several medical problems. For example, most tumour cells lose polarity, and one of the genes we have characterised is mutated in both spontaneous and inherited cancers.

Selected publications:

• Doerflinger H,Vogt N,Torres IL, Mirouse V, Koch I, Nusslein-Volhard C and St Johnston D (2010) Bazooka is required for polarisation of the Drosophila anterior- posterior axis Development 137, 1765-73

• Morais-de-Sa E, Mirouse V and St Johnston D (2010) aPKC phosphorylation of Bazooka defines the apical/lateral border in Drosophila epithelial cells Cell 141, 509-23

• St Johnston D and Ahringer J (2010) Cell polarity in eggs and epithelia: parallels and diversity Cell 141, 757- 774

• Mirouse V, Christoforou CP, Fritsch C, St Johnston D and Ray R (2009) Dystroglycan and Perlecan provide a basal cue that is required for epithelial polarity during energetic stress Dev Cell 16, 83-92

• Zimaynin VL, Belaya K, Pecreaux J, Gilchrist MJ, Clark A, Davis I and St Johnston D (2008) In vivo imaging of oskar mRNA transport reveals the mechanism of posterior localization Cell 134, 843-853

Drosophila oogenesis. A Drosophila ovariole, containing a series of germline cysts (green, BicD) that progress through oogenesis as they move posteriorly. The cysts are born at the anterior of the ovariole, and become surrounded by somatic follicle cells (red, FasIII) as they exit the germarium. Each cyst contains 16 germ cells, and one of these is selected to become the oocyte and accumulates higher levels of BicD protein.