University of Dundee

Professor Kate Storey FRSE

Neural differentiation in embryos and embryonic stem cells
Position: 
Professor of Neural Development and Head of the Division of Cell and Developmental Biology
Address: 
College of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 385691, int ext 85691
Email: 

Research

Cell division in the neural tubeDuring development cells have to become different from each other, acquiring particular characteristics in appropriate positions in the embryo. We focus on how cells acquire a neural fate and on the mechanisms that determine what type of nerve cell will form and when it will differentiate. We are using combinations of cellular and molecular techniques to investigate these processes mainly in the early chick embryo and most recently in mouse Embryonic Stem (ES) cells.

The spinal cord is generated over an extended period of time in a head to tail sequence and so is ideal for studying the temporal sequence of events that control neural differentiation. A group of cells at the tail end of embryo divide in a stem cell mode to give rise to the entire spinal cord. These stem zone cells remain in an undifferentiated state, but once cells leave this region they are able to turn on neuronal differentiation and patterning genes and some cells exit the cell cycle.We have found that the changing signalling properties of neighbouring paraxial mesoderm control differentiation onset in the extending neural axis and have identified two signalling pathways that work in opposition to control this step; Fibroblast Growth Factor (FGF) signalling maintains the undifferentiated state of the stem zone, while Retinoic acid (RA, a derivative of vitamin A) provided by segmenting mesoderm (somites) inhibits FGF signalling and drives neuron production and patterning. This FGF/RA switch appears to be a conserved differentiation event that can be identified in other embryonic tissues and is also aberrant in many cancer cell lines.

Current projects in laboratory address: i) the interaction of FGF and RA pathways, their interaction with further key signalling pathways and their regulation of cell cycle and differentiation genes; ii) cell behaviour and signalling dynamics during neurogenesis, using real- time imaging techniques; iii) regulation of neural differentiation in embryonic stem cells.

The overall aim of our work is to establish fundamental signalling networks and relationships which govern the differentiation status and behaviour of cells in the newly generated neural axis and to use these insights to investigate the molecular mechanisms that direct stable differentiation of ES cells.

Teaching

Developmental Biology (3rd year)

4 lectures:

  • Human embryonic development
  • Neural induction
  • Neural patterning
  • Wiring the nervous system
  • Vertebrate Embryology practical class (alternate years)

Publications

 

  1. Schurch, N., Cole, C., Sherstnev, A., Song, J-F., Duc, C., Storey, K.G., Brown, S., Simpson, G., Mclean, I and Barton, G.J. (2014) Improved annotation of 3’ untranslated regions and complex loci by combination of strand-specific Direct RNA Sequencing, RNA-seq and ESTs (PLoS One, Apr 10;9(4):e94270.

  2. Das, R.M. and Storey, K.G. (2014) Apical abscission alters cell polarity and dismantles the primary cilium during neurogenesis. Science 343, 200-204 (commentary Tozer & Morin 2014, Science 343, 146-147).

  3. Patel, N.S., Rhinn, M., Semprich, C I., Halley, P.A., Dollé P., Bickmore, W.A., and Storey, K.G. (2013) FGF signalling regulates chromatin organisation during neural differentiation via mechanisms that can be uncoupled from transcription PLoS Genet. 2013  9:e1003614.

  4. Olivera-Martinez I, Harada H, Halley PA, Storey KG (2012) Loss of FGF-Dependent Mesoderm Identity and Rise of Endogenous Retinoid Signalling Determine Cessation of Body Axis Elongation. PLoS Biol 10(10): e1001415. doi:10.1371/journal.pbio.1001415

  5. Halpern M.E., and Storey K.G. (2012) Layers of complexity: diverse molecular mechanisms transforming germ layers into organisms. Curr Opin Genet Dev. 2012 Aug; 22(4):305-7.

  6. Das, R.M. and Storey, K.G. (2012) Mitotic spindle orientation can direct cell fate and bias Notch activity in chick neural tube. EMBO Reports 13(5): 448-54

  7. Das, R.M., Wilcock, A.C., Swedlow, J.R., and Storey, K.G. (2012) High-resolution live imaging of cell behaviour in the developing neuroepithelium. J. Vis. Exp. (62). pii: 3920

  8. Vilas-Boas, F., Fior, R., Swedlow, J.R., Storey, K.G., and Henrique, D. (2011) A novel Reporter of Notch Signalling indicates regulated and random Notch Activation during Vertebrate Neurogenesis. BMC Biology 9:58

  9. Martínez-Morales P.L., Diez del Corral R., Olivera-Martínez, I., Quiroga, A.C., Das, R.M., Barbas, J.A., Storey, K.G., and Morales A.V. (2011) FGF and RA activity gradients control the timing of neural crest cell emigration in the trunk. J Cell Biol. 194(3), 489-503.

  10. Bouskila, M., Esoof, N., Gay, L., Fang, E.H., Deak, M., Begley, M., Cantley, L.C., Prescott, A., Storey, K.G., Alessi, D.R. (2011) TTBK2 substrate specificity and the impact of spinocerebellar ataxia-causing mutations on kinase activity, localisation and development. Biochem. J. 437, 157-67.

  11. Shiau, C.E., Das , R.M., and Storey, K.G. (2011) An effective assay for high cellular resolution time-lapse imaging of neurogenic placode formation and morphogenesis BMC Neuroscience, 12, 37.

  12. Li, R and Storey, K.G. (2011) An emerging molecular mechanism for the neural vs mesodermal cell fate decision. Cell Research, 21(5), 708-710.

  13. Stavridis, M.P., Collins, B.J. and Storey, K.G. (2010) Retinoic acid orchestrates Fibroblast growth factor signalling to drive embryonic stem cell differentiation. Development 137, 881-890.

  14. Fishwick, K.J., Li, R.A., Deng, P. Halley, P. and Storey, K.G. (2010) Initiation of neuronal differentiation requires PI3-kinase/TOR signalling in the vertebrate neural tube Developmental Biology 338, 215-225.

  15. Wilson, V., Olivera-Martinez, I. and Storey, K.G. (2009). Stem cells, signals and vertebrate body axis extension. Development 136, 1591-1604.

  16. Ekerot, M., Stavridis, M.P., Delavaine, L, Mitchell, M.P., Staples, C., Owens, D.M., Keenan, I.D., Dickinson, R.J., Storey, K.G. and Keyse, S.M. (2008) Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. Biochem J. 2, 287-98.

  17. Stavridis, M. S., Lunn, J.S., Collins, B.J. and Storey K.G. (2007) A discrete period of FGF/Erk1/2 activity is required for neural specification in embryos and ES cells. Development 134, 2889-94.

  18. Olivera-Martinez I.M., and Storey, K.G. (2007) Wnt signals provide a molecular mechanism to control the timing of the FGF/Retinoid differentiation switch. Development 134, 2125-35.

  19. Wilcock, A.C., Swedlow, J.R. and Storey, K.G. (2007) Mitotic spindle orientation distinguishes stem and terminal modes of neuron production in the early spinal cord. Development 134, 1943-54.

  20. Lunn JS, Fishwick KJ, Halley PA, Storey KG. (2007) A spatial and temporal map of FGF/Erk1/2 activity and response repertoires in the early chick embryo. Developmental Biology 302, 536-52.

  21. Smith TG, Karlsson M, Lunn JS, Eblaghie MC, Keenan ID, Farrell ER, Tickle C, Storey KG, Keyse SM (2006) Negative feedback predominates over cross-regulation to control ERK MAPK activity in response to FGF signalling in embryos. FEBS Lett. 580, 4242-5.

  22. Das, R.M., Van Hateren, N.J., Howell, G.R., Farrell, E.R., Bangs, F., Porteous, V.C., Manning, E.M., McGrew, M.J., Ohyama, K., Sacco, M.A., Halley, P.A., Sang, H.M., Storey, K.G., Placzek, M., Tickle, C., Nair, V.K. & Wilson, S.A. (2006) A robust system for RNA interference in the chicken using a modified microRNA operon Developmental Biology 294, 554-63.

  23. Akai, J., Halley, P.A. and Storey, K.G. (2005) FGF dependent Notch signalling maintains the spinal cord stem zone. Genes & Development 19, 2877-87.

  24. Collins, B.J., Deak, M.J., Murray-Tait, V., Storey, K.G. and Alessi, D.R. (2005) In vivo role of the phosphate pocket of PDK1 defined by knockin mutation. Journal Cell Science 118, 5023-34

  25. Delfino-Machin, M., Lunn, J.S., Breitkreuz, D.N., Akai, J. and Storey, K.G. (2005) Specification and maintenance of the spinal cord stem zone. Development 132, 4273-83

  26. Diez del Corral, R. and Storey, K.G. (2004) Opposing FGF and retinoid pathways: a signalling switch that controls differentiation and patterning onset in the extending vertebrate body axis (2004) Bioessays 8, 857-69.

  27. Diez del Corral, R., Olivera-Martinez, I., Goriely, A., Gale, E., Maden, M., and Storey, K (2003) Opposing FGF and Retinoid pathways control ventral neural patterning, neuronal differentiation and segmentation during body axis extension. Neuron 40, 65-79

  28. Eblaghie, M., Lunn, J.S., Dickinson, R., Munsterberg A.E., Sanz-Ezquerro, J-J., Farrell, E.R., Mathers, J., Keyse, S.M., Storey K. & Tickle, C. (2003) Negative feedback regulation of FGF signalling levels by Pyst1/MKP3 in chick embryos. Current Biology 13, 1009-1018

  29. Akai, J. and Storey, K. (2003) Brain or brawn: how FGF signaling gives us both. Cell 115, 510-2.

  30. Akai, J. and Storey, K. (2002) Expression of gamma-adducin is associated with regions of morphogenetic cell movement in the chick embryo. Mechanisms of Development 119, (S1) 191-196.

  31. Diez-del Corral, R. Breitkreuz, N. D., and Storey, K.G. (2002) Onset of neuronal differentiation in the spinal cord is regulated by the paraxial mesoderm and requires attenuation of FGF signalling. Development 129, 1681-91

  32. Storey, K.G. (2002). "Vertebrate Neurogenesis" In Molecular Basis of Patterning in Vertebrate Development: Frontiers in Molecular Biology. Ed. C. Tickle O.U.P. pp.