Professor Kim Dale FRSB
Analysis of Primitive Streak stem cells and the role of Notch in regulating cell fate choice within these multipotent progenitor pools
The broad interest of the laboratory aims to further our understanding of how several genetic interactions come into play at the earliest stages of development to build the developing embryo. Primitive streak formation is reputed as being 'the most important time in ones life' since it generates the three germ layers of the embryo proper. The progenitor cells of these three germ layers ingress into the embryonic organiser and the primitive streak where they form resident populations of stem cells for multiple tissue types. One main focus of the laboratory will be to gain a deeper understanding of the mechanism of regulation of these stem cells both in the mouse and the chick system. We will initially try to identify the location of the stem cell pools. We will then investigate the function of potential candidate signalling pathways involved in i)maintaining this stem cell state and ii) biasing these progenitors to contribute daughter cells to specific tissues inthe developing embryonic axis.
We have shown that Notch signaling is key in regulating cell fate choice within these multipotent progenitor pools which holds a promise for developing cells of desired type in in vitro ES cell culture. Following the production of the neural tube (NT), elaboration of neuronal identity begins. The NT is exquisitely patterned to eventually form the complex neuronal domains in the adult spinal cord. The correct allocation of cells to particular neuronal fates in the correct spatial location is critical for the formation of the CNS. Patterning of the NT along the dorso ventral axis into specific regionalised neuronal subtypes is primarily achieved by the morphogen Sonic hedgehog (Shh). SHH is released from two ventrally located structures which derive from the embryonic organizer, namely notochord and floor plate which results in a concentration gradient of SHH being set up along the ventral to dorsal axis which then induces expression of specific transcription factors at distinct distances from the source of the signal. We are investigating the role that Notch plays in regulating the competence of cells to respond to the SHH morphogen during DV patterning and cell fate specification in the NT.
Investigation into the molecular regulation of the Segmentation clock.
Segmentation is a universal feature of the body plan of all vertebrate species. This is most clearly seen in the vertebrate axial skeleton which is comprised of a series of segments, namely the ribs and articulating vertebrae. In vertebrate species the process of segmentation begins with the sequential formation of structures called somites, which later develop into the ribs and vertebrae. Interference with this process of somitogenesis can lead to serious segmental defects and associated pathologies, such as Spondylocostal dysostosis (SCD). The aetiology of most Abnormal vertebral segmentation (AVS) Syndromes is unknown. However one signalling pathway that has been associated with several human disorders such as SCD is the Notch signalling pathway. Somitogenesis is regulated by a molecular oscillator which drives oscillating gene expression in the paraxial mesoderm from which somites arise. The key components of the segmentation clock are intracellular components of the Notch, Wnt and FGF pathways. We have shown in mouse and chick, Notch activity is essential for both dynamic expression of all clock genes and for somite formation. Outstanding questions in the field which we are addressing are as follows:
1) Oscillating genes are negative regulators of the pathways which activate them. It seems clear how these negative feedback loops regulate oscillatory gene expression intracellularly. We are investigating how patterns of gene expression are propagated across the PSM.
2) How is the pace of clock gene oscillations regulated?
3) What is the level of cross talk and hierarchy within and between the Notch, Wnt and FGF pathways within the molecular oscillator.
161091: MYC activity is required for maintenance of the Neuromesodermal Progenitor signalling network and for correct timing of segmentation clock gene oscillations; Dale and colleagues
Where and when: the central role of Myc in somite formation
*Figure 7B (y’)
Although Myc transcription factors are extensively studied in the context of cancer, the inclusion of cMyc as one of the Yamanaka factors has renewed research into their roles in stem cell maintenance and embryogenesis. Myc is expressed throughout embryogenesis, but its spatiotemporal distribution has been poorly characterised. In this study, Kim Dale and colleagues sought to clarify the expression and function of Myc during early embryogenesis in mice, focussing on its role in body axis elongation and somite formation. The authors combine pharmacological inhibition and conditional loss-of-function genetic approaches to interrogate the role of Myc genes in the differentiation of neuromesodermal progenitors (NMPs) – a progenitor population that gives rise to posterior neural and mesoderm lineages. Their results show that cMyc is indeed required for the proper timing of somite formation through the regulation of NOTCH signalling. Additionally, they demonstrate that Myc operates in a positive feedback loop with WNT and FGF signalling in NMPs to facilitate axial elongation and to maintain accurate timing of the segmentation clock. This work places Myc activity at the centre of a signalling circuit that coordinates body axis elongation during embryogenesis.
Carrieri, F.A., Murray, P.J., Ditsova, D., Ferris, M.A., Davies, P., Dale, J.K (2019) CDK1 and CDK2 regulate NICD1 turnover and periodicity of the segmentation clock. EMBO Reports. 20, 4, p. 1-22 22 p., e46436 doi/10.15252/embr.201846436 PMID 31267714 Read Article
Murray, P., Carrieri, F.A., Dale, J.K. (2019) Cell cycle regulation of oscillations yields coupling of growth and from in a computational model of the presomitic mesoderm. Journal of Theoretical Biology. doi/10.1016/j.jtbi.2019.05.006 PMID 31121170 Read Article
Mastromina, I., Verrier L, Silva J.C, Storey K.G, and Dale J.K (2018) MYC activity is required for maintenance of the Neuromesodermal Progenitor signalling network and for correct timing of segmentation clock gene oscillations. doi/10.1242/dev.161091 PMCID 6078331 PMID 30061166 Read Article
Meakin, P. J., Jalicy, S. M., Montagut , G., Allsop, D. J. P., Cavellini, D. L.,Irvine, S. W., McGinley, C., Liddell, M. K., McNeilly, A. D., Parmionova, K., Liu, Y., Bailey, C. S. L., Dale, J. K., Heisler, L. K., McCrimmon, R. J., Ashford, M. L. J. (2018) Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice. Scientific Reports 8, Article number: 55 doi/10.1038/s41598-017-18388-6 PMCID 5758523 PMID 29311632 Read Article
Bailey, C. S. L., Bone, R. A., Murray, P. J., Dale, J. K (2017) Temporal ordering of dynamic expression data from detailed spatial expression maps. doi/10.3791/55127 PMCID 5407487 PMID 28287551 Read Article
Dale, K., Martí, E (2017) Introduction to the special section: Spinal Cord a model to understand CNS development and regeneration. doi/10.1016/j.ydbio.2017.10.005 PMID 29030145 Read Article
Carrieri FA and Dale JK (2016) Turn It Down a Notch. Front. Cell Dev. Biol. 4:151. doi/10.3389/fcell.2016.00151 PMCID 5241280 PMID 28149836 Read Article
Ellis, P.S., Burbridge, S., Soubes, S., Ohyama, K., Ben-Haim, N., Chen, C., Dale, K., Shen, M.M., Constam, D., and Placzek, M. (2015) Pro Nodal acts via FGFR3 to govern duration of Shh expression in the prechordal mesoderm. Development. 142, 3821-3832. doi/10.1242/dev.119628 PMCID 712875 PMID 26417042 Read Article
Wiedermann, G., Bone, R. A., Dale, J. K., et al. (2015) A balance of positive and negative regulators determines the pace of the segmentation clock. Elife 4: e05842. doi/10.7554/eLife.05842 PMCID 4601006 PMID 26357015 Read Article
Stasiulewicz, M., S. D. Gray, S. D., Dale, J. K., et al. (2015) A conserved role for Notch signaling in priming the cellular response to Shh through ciliary localisation of the key Shh transducer Smo. Development 142(13): 2291-2303. doi/10.1242/dev.125237 PMCID: 4510595 PMID: 25995356 Read Article
Bone, R. A., Bailey, C. S., Dale, J. K., et al. (2014) Spatiotemporal oscillations of Notch1, Dll1 and NICD are coordinated across the mouse PSM. Development 141(24): 4806-4816. doi/10.1242/dev.115535 PMCID 4299275 PMID 25468943 Read Article
Marlow, V.L., Cianfanelli, F.R., Porter, M., Cairns, L.S., Dale, J.K., and Stanley-Wall, N.R. (2014) The prevalence and origin of exoprotease-producing cells in the Bacillus subtilis biofilm. Microbiology. 160, 56-66. doi/10.1099/mic.0.072389-0 PMCID 3917226 PMID 24149708 Read Article
Maroto, M., Bone, R. A., Dale, J. K (2012) Somitogenesis. Development 139, 2453-2456. doi/10.1242/dev.069310 PMCID 3928720 PMID 22736241 Read Article
Winzi, M. K., Hyttel, P., Dale, J. K., et al. (2011) Isolation and characterization of node/notochord-like cells from mouse embryonic stem cells. Stem Cells Dev 20(11): 1817-1827. doi/10.1089/scd.2011.0042 PMCID 3928718 PMID 21351873 Read Article
Terry, A. J., Sturrock, M., Dale, J. K., Maroto, M., Chaplain, M. A. J. (2011) A spatio-temporal model of notch signalling in the zebrafish segmentation clock: conditions for synchronised oscillatory dynamics. PLoS One. 2011 Feb 28;6(2):e16980 doi/10.1371/journal.pone.0016980 PMCID 3046134 PMID 21386903 Read Article
Gibb, S.M.M., Dale, J.K. (2010) The intergration of signalling events during somitogenesis. Trends in Cell Biology, 20, 593-600.
Gray, S. D. and Dale, J. K. (2010) Notch signalling regulates the contribution of progenitor cells from the chick Hensen's node to the floor plate and notochord. Development 137(4): 561-568. doi/10.1242/dev.041608 PMCID 3928719 PMID 20110321 Read Article
Winzi, M.K., Hytell, P., Dale, J.K., and Serup, P. (2010) Isolation and characterisation of node/notochord-like cells from mouse embyonic stem cells. Stem Cells and development, 20. 1817-1827. doi/10.1089/scd.2011.0042 PMCID 3928718 PMC 21351873 Read Article
Ferjentsik, Z., Hayashi, S., Dale, J.K., Herreman, A., De Strooper, B., Bessho, Y. and Moroto, M. (2009) Notch is essential for the mouse segmentation clock. Developmental Biology, 331. doi/10.1016/j.ydbio.2009.1005.1262/1238 Read Article
Wright, D., Ferjentsik, Z., Chong, S-W., Qiu, X., Jiang, Y-J., Malapert, P., Pourquie, O., Van Hateren, N., Wilson, S.A., Franco, C., Gerhardt H., Dale, J.K., Maroto, M (2009) Cyclic Nrarp mRNA expression is regulated by the somitic ocillator but Nrarp but Nrarp protein levels do not oscillate. Dev Dyn. 238. 3043-3055. doi/10.1002/dvdy.22139 PMCID 3928721 PMID 19882724 Read Article
Maroto, M., Limura, T., Dale, J.K., Bessho, Y. (2008) bHLH proteins abd their role in somitogenesis. In "Somitogenesis". Landes Bioscience/Springer 124-139. doi.10.1007/978-0-387-09606-3 7 PMID 21038774 Read Article
Palmerim, I., Rodrigues, S., Dale, J.K., Maroto, M.(2008) Development on time. In "Cellular Oscilatory Mechanisms". Austin/New York. Landes Bioscience/Springer pp 62-68. doi/10.1007/978-0-387-09794-7 PMID 18783172 Read Article
Dale, J. K., P. Malapert, et al. (2006) Oscillations of the snail genes in the presomitic mesoderm coordinate segmental patterning and morphogenesis in vertebrate somitogenesis. Dev Cell 10(3): 355-366. doi/10.1016/j.devcel.2006.02.011 PMID: 16516838 Read Article
Dale, J. K., M. Maroto, et al. (2003) Periodic notch inhibition by lunatic fringe underlies the chick segmentation clock. Nature 421(6920): 275-278. doi/10.1038/nature01244 PMID 12529645 Read Article
Dale, J. K., C. Vesque, et al. (1997) Cooperation of BMP7 and SHH in the induction of forebrain ventral midline cells by prechordal mesoderm. Cell 90(2): 257-269. doi.org/10.1016/S0092-8674(00)80334-7 PMID 9244300 Read Article