BIOGRAPHY AND RESEARCH INTERESTS
ZFIN ID: ZDB-PERS-970204-5
We investigate molecular mechanisms that control the spatial patterning of cell differentiation and cell migration, using the hindbrain as a simple model. We are analysing how the neural epithelium becomes segmented into regional domains, how subdivisions become refined into a precise organisation of cell types, and how these patterns are stabilised by the control of cell movement. Our work divides into three main areas: (1) Analysis of developmental roles of Eph receptors and ephrins in the control of cell movement, and the mechanisms by which they mediate both cell repulsion and cell adhesion responses; (2) Regulatory networks that control the patterning of neurogenesis, with a current focus on Notch and wnt genes and the formation and functions of boundary cells; (3) Screens and functional analyses of novel genes involved in hindbrain patterning. Most of our work uses the zebrafish system due to its advantages for rapid analysis of gene function, availability of mutants, and in vivo imaging of cell behaviour and transgene expression. In addition, we carry out experiments in chick embryos to compare developmental mechanisms and to use the specific advantages of this system.
David Wilkinson has studied a range of developmental systems. His Ph.D. studies at the University of Leeds were on cell differentiation in Dictyostelium, and postdoctoral research at the Fox Chase Cancer Center, Philadelphia, analysed spatially regulated genes in sea urchin embryogenesis. He then moved to the National Institute for Medical Research, London, where he developed in situ hybridisation methods to study gene expression during mouse development. This work uncovered the spatial expression of the wnt1, FGF3 and Brachyury genes, and led to the discovery of segmental gene expression in the hindbrain (Krox20 and Hox genes). Subsequent gene expression screens in mouse, and functional studies in Xenopus and zebrafish revealed the segmental expression of Eph receptors and ephrins, and their roles in restricting cell movement across boundaries. Recent work has uncovered roles of boundaries in the control of cell differentiation in the zebrafish hindbrain. David Wilkinson is Head of the Division of Developmental Neurobiology, and of the Genetics and Development group of Divisions at the NIMR.
Jacob, J., Ribes, V., Moore, S., Constable, S.C., Sasai, N., Gerety, S.S., Martin, D.J., Sergeant, C.P., Wilkinson, D.G., and Briscoe, J. (2014) Valproic Acid silencing of ascl1b/ascl1 results in the failure of serotonergic differentiation in a zebrafish model of Fetal Valproate Syndrome. Disease models & mechanisms. 7(1):107-17
John, J., Ribes, V., Moore, S., Constable, S., Wilkinson, D., Briscoe, J. (2013) A chemical-genetics approach to study the molecular pathology of central serotonin abnormalities in fetal valproate syndrome. Journal of neurology, neurosurgery, and psychiatry. 84(11):e2
Gerety, S.S., Breau, M.A., Sasai, N., Xu, Q., Briscoe, J., and Wilkinson, D.G. (2013) An inducible transgene expression system for zebrafish and chick. Development (Cambridge, England). 140(10):2235-2243
Moore, S., Ribes, V., Terriente, J., Wilkinson, D., Relaix, F., Briscoe, J. (2013) Distinct regulatory mechanisms act to establish and maintain Pax3 expression in the developing neural tube. PLoS Genetics. 9:e1003811
Terriente, J., Gerety, S.S., Watanabe-Asaka, T., Gonzalez-Quevedo, R., and Wilkinson, D.G. (2012) Signalling from hindbrain boundaries regulates neuronal clustering that patterns neurogenesis. Development (Cambridge, England). 139(16):2978-2987
Nikolaou, N., Watanabe-Asaka, T., Gerety, S., Distel, M., Köster, R.W., and Wilkinson, D.G. (2009) Lunatic fringe promotes the lateral inhibition of neurogenesis. Development (Cambridge, England). 136(15):2523-2533
Cheng, Y.C., Amoyel, M., Qiu, X., Jiang, Y.J., Xu, Q., and Wilkinson, D.G. (2004) Notch activation regulates the segregation and differentiation of rhombomere boundary cells in the zebrafish hindbrain. Developmental Cell. 6(4):539-550
Manzanares, M., Trainor, P.A., Nonchev, S., Ariza-McNaughton, L., Brodie, J., Gould, A., Marshall, H., Morrison, A., Kwan, C.-T., Sham, M.-H., Wilkinson, D.G., and Krumlauf, R. (1999) The role of kreisler in segmentation during hindbrain development. Developmental Biology. 211(2):220-237
Wilkinson, D.G., Bailes, J.A. and McMahon, A.P. (1987) Expression of the proto-oncogene int-1 is restricted to specific neural cells in the developing mouse embryo. Cell 50, 79-88.
Wilkinson, D.G., Peters, G., Dickson, C. and McMahon, A.P. (1988) Expression of the FGF-related proto-oncogene int-2 during gastrulation and neurulation in the mouse. EMBO J. 7, 691-695.
Wilkinson, D.G., Bhatt, S., Chavrier, P., Bravo, R. and Charnay, P. (1989) Segment-specific expression of a zinc finger gene in the developing nervous system of the mouse. Nature 337, 461-465.
Wilkinson, D.G., Bhatt, S., Cook, M., Boncinelli, E. and Krumlauf, R. (1989) Segmental expression of Hox-2 homoeobox-containing genes in the developing mouse hindbrain. Nature 341, 405-409.
Wilkinson, D.G., Bhatt, S. and Herrmann, B.G. (1990) Expression pattern of the mouse T gene and its role in mesoderm formation. Nature 343, 657-659.
Hunt, P., Gulisano, M., Cook, M., Sham, M.-H., Faiella, A., Wilkinson, D.G., Boncinelli, E. and Krumlauf, R. (1991) A distinct Hox code for the branchial region of the vertebrate head. Nature 353, 861-864.
Nieto, M.A., Bennett, M., Sargent, M. and Wilkinson, D.G. (1992) Cloning and developmental expression of Sna, a murine homologue of the Drosophila snail gene. Development 116, 227-237.
Nieto, M.A., Gilardi-Hebenstreit, P., Charnay, P. and Wilkinson, D.G. (1992) A receptor protein tyrosine kinase implicated in the segmental patterning of the hindbrain and mesoderm. Development 116, 1137-1150.
Nieto, M.A., Sargent, M., Wilkinson, D.G. and Cooke, J. (1994) Control of cell behavior during vertebrate development by Slug, a zinc finger gene. Science 264, 835-839.
Flenniken, A.M., Gale, N.W., Yancopoulos, G.D. and Wilkinson, D.G. (1996) Distinct and overlapping expression of ligands for Eph-related receptor tyrosine kinases during mouse embryogenesis. Dev. Biol. 179, 382-401.
Gale, N.W., Holland, S.J., Valenzuela, D.M., Flenniken, A., Pan, L., Henkemeyer, M., Strebhardt, K., Hirai, H., Wilkinson, D.G., Pawson, T., Davis, S. and Yancopoulos, G.D. (1996) Eph receptors and ligands comprise two major specificity subclasses, and are reciprocally compartmentalised during embryogenesis. Neuron 17, 9-19.
Smith, A., Robinson, V., Patel, K. and Wilkinson, D.G. (1997) The EphA4 and EphB1 receptor tyrosine kinases and ephrin-B2 ligand regulate targeted migration of branchial neural crest cells. Current Biology 7, 561-570.
Theil, T., Frain, M., Gilardi-Hebenstreit, P., Flenniken, A., Charnay, P. and Wilkinson, D.G. (1998) Segmental expression of the EphA4 (Sek-1) receptor tyrosine kinase in the hindbrain is under direct transcriptional control of Krox-20. Development 125, 443-452.
Theil, T., Ariza-McNaughton, L., Manzaneres, M., Brodie, J., Krumlauf, R. and Wilkinson, D.G. (2002) Requirement for downregulation of kreisler during late patterning of the hindbrain. Development 129, 1477-1485.
Coles, E., Christiansen, J., Economou, A., Bronner-Fraser, M. and Wilkinson, D.G. (2004) A vertebrate crossveinless-2 homologue modulates BMP activity and neural crest cell migration. Development 131, 5309-5317.
Poliakov, A., Cotrina, M. and Wilkinson, D.G. (2004) Diverse roles of Eph receptors and ephrins in the regulation of cell migration and tissue assembly. Developmental Cell 7, 465-480.