University of Dundee

Professor Kees Weijer FRSE

Cell-cell signalling and chemotactic cell movement during development
Position: 
Professor of Developmental Physiology and Head of Systems Biology
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 385191, int ext 85191
Email: 

Research

Cell movement plays an essential role in the embryonic development of multicellular organisms, especially during gastrulation, formation of the nervous system and organogenesis. When not properly controlled it results in severe congenital defects and disease in later life. Cell movement is often guided by gradients of diffusible attractive and repulsive signalling molecules (chemotaxis). Important open questions are how do cells after detection of gradients of chemo-attractants/repellents translate this information in polarised organisation of the actin myosin cytoskeleton to result in directed movement up or down these signalling gradients?. A further key question is how chemotactic signalling and cell movement interact to create new tissues? We study these questions using a variety of multidisciplinary approaches in two model organisms, the genetically tractable social amoebae Dictyostelium discoideum and during gastrulation in the chick embryo.

Dictyostelium cells show very efficient homologies recombination, allowing the fast generation of targeted gene disruptions and replacements. We use these techniques in combination with high resolution SILAC based proteomics, TIRF and confocal imaging, dedicated microfluidic devices and detailed mathematical modelling to to study the molecular basis of serpentine receptor mediated chemotactic signal transduction to and organisation of the actin-myosin cytoskeleton (fig. 1). Dictyostelium cells do not only detect and move in response to the chemo-attractant cAMP, but they can also amplify and pass on cAMP signals to neighbouring cells, a process that results in the generation of propagating waves of cAMP (fig. 1). We study how these interactions between cAMP wave propagation and cell movement result in emergent behaviours and morphogenesis at the tissue level using again molecular genetics, advanced imaging and detailed mathematical modelling

Figure 1: Aggregation of Dictyostelium cells is coordinated by propagating waves of cAMP, which can be visualised through their associated dark field waves. These darkfield waves reflect bands of moving and non-moving cells. The waves propagate from the centres outward (blue arrows in A) and direct the inward motion of the cells towards the aggregation centre (red arrows). Cells in a cAMP wave polarise, they produce PIP3 in the front (B, D), which is stabilised by PTEN localising to the back of the cells (C). Cell movement in slugs is also organised by waves propagating from the tip to the slug posterior and in slugs (E) Slug cells also polarise by making PIP3 (F) in the front of the cells and localising PTEN to the back (G). Slug cells make cell-cell and cell-matrix contacts that are required for getting traction during movement (H).

To study cell movement during gastrulation in the chick embryo we use a combination of advanced in-vivo imaging methods and computational data analysis and modelling techniques. We have designed and build a lightsheet microscope that allows us to image all (>100.000) cells in the early chick embryo and to analyse their individual behaviours over extended periods of time (fig 2). These massive data sets allow us to understand how the behaviour of so many cells is coordinated and integrated to result in the large scale tissue flows and deformations that underlie the formation of the primitive streak. Furthermore we are characterising the movement of mesoderm cells after their ingression through the streak (fig 3). Our results show that their complex movements appears to be controlled by a sequential combination of positive and negative chemotactic responses to different FGF’s and VEGF’s and also involves other as yet uncharacterised chemo-attractants.  

Figure 2: Light sheet microscopy to study tissue dynamics during chick gastrulation. A: schematic of lightsheet microscope showing the orthogonal illumination and imaging axes. B: upper image sequence showing dividing cell (red dot) at 10x, lower image sequence showing ingressing cell (red dot). C: Overview image of early chick embryo derived from 3000 optical sections take every 2 minutes. The arrows indicate the direction and magnitude of epiblast tissue flow as calculated by Particle Image Velocimetry (PIV). D: blow up of centre of vortex show in red box in C

Figure 3: Migration of cells in mesoderm cells during the early stages of gastrulation. A: Image of a stage HH3 embryo directly after grafting a piece of middle streak tissue from a transgenic GFP expressing chick embryo of a similar stage in a homotypic position photograph of cell shape of GFP graft. B: Image of the same embryo after 20 hours incubation in culture. Most of the cells have migrated out of the streak where they will form the vasculature in the Area Opaca. The most anterior cells have stated to migrate back to participate in the formation of the embryonic vasculature. C: Higher magnification image of cells in the process of migrating out of the streak. It can be clearly seen that the cells are in close contact and highly polarised in the direction of migration. D: High magnification image of a few mesoderm cells at the edge of the cohort. Notice the very extensive cellular processes. E: Composite image of typical migration patterns observed of cell migrating from different antero-posterior positions in the streak during development from stage HH4 to stage HH7 (20 hours). Cells in the anterior streak migrate outward and then back in to form the somites (red tracks). Cells from the middle streak migrate out to form lateral plate mesoderm (yellow tracks) and cells located in the posterior streak migrate out in the extra-embryonic area to form the vasculature (green tracks).

Teaching

BS31004 - Biochemistry and Cell Biology

BS32005 - Developmental Biology

Publications

Belotti Y.,  McGloin D., and  Weijer C.J., (2020) Analysis of barotactic and chemotactic guidance cues on directional decision-making of Dictyostelium discoideum cells in confined environments. Proc Natl Acad Sci USA doi.org/10.1073/pnas.2000686117 Read Article

Serrano Nájera, G., Weijer, C.J., (2020) Cellular processes driving gastrulation in the avian embryo. doi/10.1016/j.mod.2020.103624 PMID: 32562871  Read Article

Serra, M., Streichan, S., Chuai, M., Weijer, C.J., and Mahadevan., L (2020) Dynamic morphoskeletons in development. Proc Natl Acad Sci USA May 26, 2020 117 (21) 11444-11449; https://doi.org/10.1073/pnas.1908803117 PMID 32381735  Read Article

Ferro, V.,  Chuai, M., McGloin, D., Weijer, C.J (2020) Measurement of junctional tension in epithelial cells at the onset of primitive streak formation in the chick embryo via non-destructive optical manipulation. Development 2020 147. doi: 10.1242/dev.175109 PMID 31964776 Read Article

Singer, G., Araki, T. and Weijer, K (2019) Oscillatory cAMP cell-cell signalling persists during multicellular Dictyostelium development.  Communications Biology, vol.2, 139, pp 1-12. doi.org/10.1038/s42003-019-0371-0 PMCID 6478855 PMID 31044164 Read Article

Weijer, C.J (2019) Spiral Waves of the Chemo-Attractant cAMP Organise Multicellular Development in the Social Amoebae Dictyostelium discoideum. Spirals and Vortices pp 193-207 Read Article

Barton, D.L., Henkes, S., Weijer, C.J., Sknepnek, R. (2017) Active vertex module for cell-resolution description of epithelial tissue mechanics. PLOS Comput Biol 13(6): e1005569.  doi.org/10.1371/journal.pcbi.1005569 PMCID 549329  PMID 28665934 Read Article

Reidt, S., Bango Da Cunha Correia, R., Donnachie, M., Weijer, C.J., MacDonald, M. (2017) Gaussian vs. Bessel light-sheets: performance analysis in live large sample imaging. Optical Trapping and Optical Micromanipulation XIV 1034709.  doi/10.1117/12.2277324 Read Article

Bretschneider, T., Othmer, H.G. and Weijer, C.J. (2016) Progress and perspectives in signal transduction, actin dynamics and movement at the cell and tissue level: lessons from Dictyostelium.  Interface Focus. 6, 20160047.  doi/10.1098/rsfs.2016.0047 PMCID 4992746 PMID 27708767 Read Article

Glockner, G., Lawal, H.M., Felder, M., Singh, R., Singer, G., Weijer, C.J and Schaap, P. (2016) The multicellularity genes of dictyostelid social amoebas.  Nature Communications. 7, 12085.  doi/10.1038/ncomms12085 PPMCID 4931340 MID 27357338 Read Article

Hughes, DA, Qiu, Y, Démoré, C, Weijer, C.J. & Cochran, S (2015) Alignment of an acoustic manipulation device with cepstral analysis of electronic impedance data. Ultrasonics, vol. 56, pp. 172-177. doi.org/10.1016/j.ultras.2014.09.017 PMID 25448425 Read Article

Pineda, M, Weijer, C.J. & Eftimie, R (2015) Modelling cell movement, cell differentiation, cell sorting and proportion regulation in Dictyostelium discoideum aggregations' Journal of Theoretical Biology, vol. 370, pp. 135-150. doi.org/10.1016/j.jtbi.2015.01.042  PMID 25665718 Read Article

Rozbicki E, Chuai M, Karjalainen AI, Song F, Sang HM, Martin R, Knölker HJ, MacDonald MP, and Weijer C.J. (2015) Myosin-II-mediated cell shape changes and cell intercalation contribute to primitive streak formation. Nat. Cell. Biol 17, 397 – 408.  doi/10.1038/ncb3138 PMCID 4886837 PMID: 25812521 Read Article

Du CJ, Tyson RA, Rozbicki E, Weijer C.J, Bretschneider T. (2014) Multi-Scale Non-Local Means with Shape Prior for Enhancement of Cell Membrane Images. 2014 IEEE 11th International Symposium on Biomedical Imaging (ISBI). pp 493-496. doi/10.1109/isbi.2014.6867916 Read Article

Sobczyk GJ, Wang J, Weijer C.J (2014) SILAC-based proteomic quantification of chemoattractant-induced cytoskeleton dynamics on a second to minute timescale.  Nat Commun. 2014 Feb 26; 5:3319.  doi/10.1038/ncomms4319 PMCID 3971484 PMID 24569529 Read Article

Chuai M, Hughes D, Weijer C.J (2012) Collective Epithelial and Mesenchymal Cell Migration during Early Embryogenesis.Current Genetics 13, 267-27. doi/10.2174/138920212800793357 PMCID 3394114 PMID 23204916 Read Article

Sandersius SA, Chuai M, Weijer C.J, Newman TJ. (2011) A 'chemotactic dipole' mechanism for large-scale vortex motion during primitive streak formation in the chick embryo. Phys Biol. Aug; 8(4):045008. Epub 2011 Jul 12. doi/10.1088/1478-3975/8/4/045008 PMID 21750368 Read Article

Sandersius SA, Chuai M, Weijer C.J, Newman TJ (2011) Correlating cell behavior with tissue topology in embryonic epithelia. PLoS One Apr 29; 6(4):e18081. doi/10.1371/journal.pone.0018081 PMCID 3084706 PMID 21559520 Read Article

Davidson L, Maccario H, Perera NM, Yang X, Spinelli L, Tibarewal P, Glancy B, Gray A, Weijer C.J, Downes CP and Lesie NR (2010) Suppression of cellular proliferation and invasion by the concerted lipid and protein phosphatase activities of PTEN. Oncogene 29(5):687-697. doi/10.1038/onc.2009.384 PMCID 2816976 PMID 19915616 Read Article

Vasiev B, Balter A, Chaplain M, Glazier JA and Weijer C.J (2010) Modeling gastrulation in the chick embryo: formation of the primitive streak. PLoS One 5(5):e10571. doi/10.1371/journal.pone.0010571 PMCID 2868022 PMID 20485500 Read Article

Chuai M and Weijer C.J (2009) Regulation of cell migration during chick gastrulation.  Current opinion Gene & development Volume 19, Issue 4 (2009) 343-349. doi/10.1016/j.gde.2009.06.007 PMID 19647425 Read Article

Chuai M and Weijer C.J (2009) Who moves whom during primitive streak formation in the chick embryo. HFSP J 3(2):71-76. doi/10.2976/1.3103933 PMCID 2707795 PMID 19794819 Read Article

Chuai M, Dormann, D, and Weijer C.J (2009) Imaging cell signalling and movement in development. Semin Cell Dev Biol 20(8):947-55. doi/10.1016/j.semcdb.2009.09.001 PMID 19747557 Read Article

Weijer, C.J (2009) Collective cell migration in development. J of Cell Science. 122(18):3215-3223. doi/10.1242/jcs.036517 PMID 19726631 Read Article

Yang, XS, Chrisman H and Weijer C.J (2008) PDGF signalling controls the migration of mesoderm cells during chick gastrulation by regulating N-cadherin expression. Development 135(21):3521-3530.  doi/10.1242/dev.023416 PMID 18832396 Read Article

Chuai M, Weijer C.J (2008) The mechanisms underlying primitive streak formation in the chick embryo.Curr Top Dev Biol.81:135-56. doi/10.1016/S0070-2153(07)81004-0 PMID 18023726 Read Article

Iimura T, Yang X, Weijer C.J, Pourquié O. (2007) Dual mode of paraxial mesoderm formation during chick gastrulation. Proc Natl Acad Sci U S A. 104:2744-9. doi/10.1073/pnas.0610997104 PMCID 1815252 PMID 17299044 Read Article

Leslie NR, Yang X, Downes CP, Weijer C.J (2007) PtdIns(3,4,5)P(3)-dependent and -independent roles for PTEN in the control of cell migration. Curr Biol. 17:115-25. doi.org/10.1016/j.cub.2006.12.026 PMCID PMC1885949 PMID 17240336 Read Article

Dormann D, Weijer C.J (2006) Imaging of cell migration. EMBO J. 25:3480-93. doi/1038/sj.emboj.7601227 PMCID 1538568 PMID 16900100 Read Article

Chuai M, Zeng W, Yang X, Boychenko V, Glazier JA, Weijer C.J (2006) Cell movement during chick primitive streak formation.Dev Biol. 296:137-49. doi/10.1016/j.ydbio.2006.04.451 PMCID 2556955 PMID 16725136 Read Article

Bukahrova T, Weijer G, Bosgraaf L, Dormann D, van Haastert PJ,  (2005) Paxillin is required for cell-substrate adhesion, cell sorting and slug migration during Dictyostelium development. J Cell Sci. 118:4295-310. doi/10.1242/jcs.02557 PMID 16155255 Read Article

Affolter M, Weijer C.J (2005) Signaling to cytoskeletal dynamics during chemotaxis. Dev Cell.9:19-34. doi/10.1016/j.devcel.2005.06.003 PMID 15992538 Read Article

Cui C, Yang X, Chuai M, Glazier JA, Weijer C.J (2005) Analysis of tissue flow patterns during primitive streak formation in the chick embryo. Dev Biol. 284: 37-47. doi/10.1016/j.ydbio.2005.04.021 PMID 15950214 Read Article

Dormann D, Weijer G, Dowler S, Weijer C.J (2004) In vivo analysis of 3-phosphoinositide dynamics during Dictyostelium phagocytosis and chemotaxis. J Cell Sci.;117:6497-509. doi/10.1242/jcs.01579 PMID 15572406 Read Article

Dormann, D. and Weijer C.J (2001) Propagating chemoattractant waves coordinate periodic cell movement in Dictyostelium slugs. Development, 128: 4535-43. PMID: 11714678 Read Article

Patel, H, Weijer C.J et al (2000) A temperature-sensitive adenylyl cyclase mutant of Dictyostelium. Embo Journal, 19: 2247-2256. doi/10.1093/emboj/19.10.2247 PMCID 384365 PMID 10811616 Read Article

Dormann, D, Weijer C.J, et al. (2001) Inducible nuclear translocation of a STAT protein in Dictyostelium prespore cells: implications for morphogenesis and cell-type regulation. Development, 128: 1081-1088. PMID 11245573 Read Article

Yang, X, Weijer C.J, et al (2002) Cell movement patterns during gastrulation in the chick are controlled by positive and negative chemotaxis mediated by FGF4 and FGF8. Dev Cell, 3: 425-437. doi.org/10.1016/S1534-5807(02)00256-3 PMID 12361604 Read Article

Dormann, D, Weijer C.J, et al (2002) Visualizing PI3 kinase-mediated cell-cell signaling during Dictyostelium development. Curr Biol, 12: 1178-88. doi.org/10.1016/S0960-9822(02)00950-8 PMID 12176327 Read Article