- Phone : +1 (416) 978-4539
- Email : brenda.coles@utoronto.ca
- Address : 160 College Street, 11th floor Donnelly Centre
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Cell Lineage and Neural Development
Our objective is to understand where brains come from. We plan to address the questions of how the neural stem cell fate is maintained, how definitive (brain derived) neural stem cells acquire regional identity, and whether this regional identity (and indeed even the neural stem cell state itself) is plastic.
Neural stem cells (NSCs) reside in the tissue lining the lateral ventricles of the adult mouse brain. At the top of the hierarchy are primitive NSCs that appear during early embryonic development and are able to give rise to the definitive NSCs. Primitive neural stem cells (both embryo derived & in vivo derived) show considerable non-neural tissue plasticity. However, definitive (brain derived) neural stem cells have less non-neural tissue plasticity, but still show plasticity in their commitment to a neural regional fate along the anteroposterior neuroaxis. We are exploring what genes and regulatory pathways may underlie the stem cell identity and the ability of the progeny to go down different lineage pathways using single cell RNA sequencing of both the primitive and definitive neural stem cells and their progeny.
We also are studying cells that are made by reprogramming somatic cells via the overexpression of key transcription factors (and referred to as Induced Pluripotent Stem Cells (iPSCs) or induced neurons). However, are all cells equally capable of being reprogrammed or is there an “elite” type of cell that is more primed to this conversion process? We have shown that the neural crest stem cells appear to be this elite somatic cell type and may account for the majority of cell reprogramming in the field. We currently are using lineage-tracing in animal models to explore this possibility.
Related Publications:
Yammine S, Burns I, Gosio J, Peluso A, Merritt D, Innes B, Coles B, Yan WR, Bader GD, Morshead C, van der Kooy D. (2023). Fate specification of GFAP-negative primitive neural stem cells and their progeny at clonal resolution. Stem Cells and Development.https://doi.org/10.1089/scd.2023.0038
Shakiba N, Fahmy A, Jayakumaran G, McGibbon S, David L, Trcka D, Elbaz J, Puri MC, Nagy A, van der Kooy D, Goyal S, Wrana JL, Zandstra PW. (2019). Cell competition during reprogramming gives rise to dominant clones. Science. 364(6438):eaan0925. https://doi.org/10.1126/science.aan0925
Baker AEG, Cui H, Ballios BG, Ing S, Yan P, Wolfer J, Wright T, Dang M, Gan NY, Cooke MJ, Ortín-Martínez A, Wallace VA, van der Kooy D, Devenyi R, Shoichet MS. (2021). Stable oxime-crosslinked hyaluronan-based hydrogel as a biomimetic vitreous substitute. Biomaterials. 271: 120750.https://doi.org/10.1016/j.biomaterials.2021.120750
Ahuja AS, Mothe A, Khazaei M, Badhiwala J, Gilbert EA, van der Kooy D, Morshead CM, Tator C, Fehlings M. (2020). The leading edge - emerging neuroprotective and neuroregenerative cell-based therapies for spinal cord injury. Stem Cells Translational Medicine. 9: 1509-1530.https://doi.org/10.1002/sctm.19-0135
Clarke, L., van der Kooy, D. The adult mouse dentate gyrus contains populations of committed progenitor cells that are distinct from subependymal zone neural stem cells. Stem Cells 29 (2011) 1448-58. (clarke...2011...)
Akamatsu, W., Cooney, A.J., van der Kooy, D. Suppression of Oct4 by germ cell nuclear factor promotes the development of the early neural stem cell lineage. Journal of Neuroscience. 29 (2009) 2113-2124. (akamatsu...2009...)
Smukler SR, Runciman SB, Xu S, van der Kooy D. Embryonic stem cells assume a primitive neural stem cell fate in the absence of extrinsic influences. Journal of Cell Biology 172 (2006) 79-90. (smukler...2006...)
Hitoshi S, Seaberg RM, Koscik C, Alexson T, Kusunoki S, Kanazawa I, Tsuji S, van der Kooy D.Primitive neural stem cells from the mammalian epiblast differentiate to definitive neural stem cells under the control of Notch signaling. Genes Dev. 2004 Aug 1;18(15):1806-11. (hitoshi...2004)
V. Tropepe, S. Hitoshi, C. Sirard, T. Mak, J. Rossant, van der Kooy D. Direct neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism. Neuron. 2001 Apr;30(1):65-78. (tropepe...2001)