Daniel St Johnston PhD FRS FMedSci, Chairman
Daniel is Professor of Developmental Genetics in the Department of Genetics
Cell polarity, the cytoskeleton and mRNA localisation
Co-workers: Dan Bergstralh • Jia Chen • Hélène Doerflinger • Weronica Fic • Alejandra Gardiol • Timm Haack • Jackie Hall • Holly Lovegrove • Nick Lowe • Avik Mukherjee • Dmitry Nashchekin • Artur Ribeiro Fernandes • Aram Sayadian • Vanessa Stefanak • Vitor Trovisco • Yu Ye
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.
Cell polarity is essential for most cell functions and for several key developmental processes, such as cell migration, axis determination and asymmetric stem cell divisions, whereas loss of polarity is a critical step in the formation of tumours. We use Drosophila and mammalian tissue culture cells to analyse how cells become polarised and how this polarity controls the organisation of the cytoskeleton and intracellular trafficking.
Much of our work focuses on apical-basal polarity in epithelial cells, since these are the most common animal cell-type and must polarise to adhere to each other to form sheets of cells that act as barriers between compartments. As a model, we use the follicle cells that surround the developing egg chamber, as these form a typical secretory epithelium that is continuously generated from adult stem cells, making it easy to produce mutant clones. We are screening for novel polarity factors and investigating how cortical polarity controls spindle orientation, the organisation of the microtubule cytoskeleton and polarised secretion. We are also investigating polarity in the adult midgut, an absorptive epithelium, in which apical-basal arrangement of intercellular junctions is different.
In parallel, we are examining how the Drosophila oocyte is polarised, since the localisation of bicoid and oskar mRNAs to opposite ends of this very large cell defines the anterior-posterior axis of the embryo. We use genetic, proteomic and biochemical approaches to elucidate how conserved polarity proteins regulate the organisation of the microtubule cytoskeleton in the oocyte, and analyse the mechanisms of mRNA transport and nuclear movement by making time-lapse films of moving mRNA particles and microtubule end markers in wildtype and mutant oocytes.
• Zhao T, Graham O, Raposo A and St Johnston D (2012) Growing microtubules push the oocyte nucleus to polarize the Drosophila dorsal-ventral axis. Science , 336, 999-1003.
• St Johnston D (2012) Using mutants, knockdowns, and transgenesis to investigate gene function in Drosophila. WiRES Developmental Biology , doi: 10.1002/wdev.101.
• Rees JS, Lowe N, Armean IM, Roote J, Johnson G, Drummond E, Spriggs H, Ryder E, Russell S, St Johnston D and Lilley KS (2011) In vivo analysis of proteomes and interactomes using Parallel Affinity Capture (iPAC) coupled to mass spectrometry. Molecular Cell Proteomics , 10, M110 002386.
• St Johnston D and Sanson B (2011) Epithelial polarity and morphogenesis. Current Opinion in Cell Biology ,23, 540?546.
• Chang CW, Nashchekin D, Wheatley L, Irion U, Dahlgaard K, Montague TG, Hall J and St Johnston D (2011) Anterior-posterior axis specification in Drosophila oocytes: identification of novel bicoid and oskar mRNA localisation factors. Genetics ,188: 883-898