The assembly and maintenance of the mammalian brain by neural precursor cells (NPCs), are tightly regulated processes, which involve integration of intrinsic transcriptional programs with extrinsic information from the cellular microenvironment to ensure that the correct cell types are produced, at the right time, to establish functional circuits.
Our major goal is to understand using a mixture of neurobiological, high-throughput and bioinformatic approaches how NPCs, sense their microenvironments, interpret this information and ultimately decide how to respond accordingly. Understanding how extrinsic cues control NPCs has the potential to inform novel therapeutic strategies aimed at activating these cells for repair following brain injury or disease.
We are pursuing research in two inital areas:
First, we have recently identified using high-throughput single-cell RNA-sequencing, a key ‘on/off’ switch which controls proliferation of radial precursor (RPs) cells in the developing brain by modulating their response to the cellular microenvironment. We aim to understand how this switch allows RPs to become ‘slow-dividing’ and persist into the adult brain to give rise to adult neural stem cells (NSCs). Leveraging a deep understanding of this ‘on/off switch,’ we aim to develop approaches to force this switch into the ‘off’ position thereby mobilizing NSCs following brain injury or disease.
Second, tissue resident stem cells such as adult NSCs are housed in specialize niche microenvironments with well defined cellular architectures. Spatial information is therefore critical in understanding the identity and sources of extrinsic cues which control NSC cell fate decisions. We are developing and applying methods to add spatial level information to single-cell transcriptomic data and thereby reveal the complexity of extrinsic regulation in the NSC niche.
Department of Laboratory Medicine & Pathobiology, University of Toronto
Previous Institution: University of Toronto - Mississauga
Daniela Lozano Casasbuenas
LMP SURE Program Summer Student May-Aug 2019.
Currently: Undergraduate at McMaster University.
Undergraduate Research Assistant May 2019-Mar 2020.
Currently: Undergraduate at University of Toronto.
Undergraduate Volunteer Fall 2019.
Currently: Undergraduate at University of Toronto.
Full Publication list can be found on Google Scholar
1. Jeong D, Lozano Casasbuenas D, Gengatharan A, Edwards K, Saghatelyan A, Kaplan DR, Miller FD, Yuzwa SA. "LRIG1-Mediated Inhibition of EGF Receptor Signaling Regulates Neural Precursor Cell Proliferation in the Neocortex." Cell Reports 33(2):108257 (2020).
2. Carr MJ, Toma JS, Johnston APW, Steadman PE, Yuzwa SA, Mahmud N, Frankland PW, Kaplan DR, Miller FD. "Mesenchymal Precursor Cells in Adult Nerves Contribute to Mammalian Tissue Repair and Regeneration." Cell Stem Cell 24(2):240-256.e9 (2019).
3. Zahr SK, Yang G, Kazan H, Borrett MJ, Yuzwa SA, Voronova A, Kaplan DR, Miller FD. "A translational repression complex in developing mammalian neural stem cells that regulates neuronal specification." Neuron (97) 520-537 (2018).
4. Yuzwa SA*, Borrett MJ*, Innes BT, Voronova A, Ketela T, Kaplan DR, Bader GD, Miller FD. "Developmental emergence of adult neural stem cells as revealed by single cell transcriptional profiling." Cell Reports (21) 3970-3986 (2017) *Indicates equal contribution.
5. Voronova A, Yuzwa SA, Wang B, Zahr S, Syal C, Wang J, Kaplan DR, Miller FD. "Migrating Interneurons Secrete Fractalkine to Promote Oligodendrocyte Formation in the Developing Mammalian Brain." Neuron (94) 500-516 (2017).
6. Ravindran E, Hu H, Yuzwa SA, Hernandez-Miranda LR, Kraemer N, Ninnemann O, Musante L, Boltshauser E, Schindler D, Hübner A, Reinecker H, Ropers H, Birchmeier C, Miller FD, Wienker TF, Hubner C, Kaindl AM "Homozygous ARHGEF2 Mutation Causes Intellectual Disability and midbrain-hindbrain malformation" PLOS Genetics 13(4) e1006746 (2017).
7. Yuzwa SA*, and Miller FD*. "Deciphering cell-cell communication in the developing mammalian brain." Neurogenesis 4(1) e1286425 (2017) *Indicated co-corresponding author.
8. Yuzwa SA.*, and Vocadlo DJ. "Production of O-GlcNAc modified recombinant tau in E.coli and detection of Ser400 O-GlcNAc tau in vivo." Methods in Molecular Biology: Tau Protein (1523) 237-248 (2017). *Indicates corresponding author.
9. Yuzwa SA, Yang G, Borrett M, Clarke G, Cancino GI, Zahr S, Zandstra PW, Kaplan DR, Miller FD. "Proneurogenic Ligands Defined by Modeling Developing Cortex Growth Factor Communication Networks." Neuron (91) 988-1004 (2016).
10. Johnston APW, Yuzwa SA*, Carr M*, Krause MP, Mahmud N, Storer MA, Jones K, Paul S, Kaplan DR, Miller FD. "Dedifferentiated Schwann Cell Precursors Secreting Paracrine Factors Are Required for Regeneration of the Mammalian Digit Tip." Cell Stem Cell (19) 433-448. (2016). *Indicates equal contribution.
11. Naska S*, Yuzwa SA*, Johnston APW, Paul S, Smith K, Paris M, Datti A, Miller FD, Kaplan DR. "Identification of drugs that regulate dermal stem cells and enhance skin repair." Stem Cell Reports 6(1) 74-84 (2016). *Indicates equal contribution.
12. Yuzwa SA*, Shan X*, Jones BA, Zhao G, Li X, McEachern EJ, Watson NV, Gong C-X, Vocadlo DJ. "Pharmacological Inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice." Mol Neurodegener 9(42) (2014) *Indicates equal contribution.
13. Yuzwa SA*, Cheung A*, Okon M, McIntosh L, Vocadlo DJ. "O-GlcNAc modification of tau directly inhibits its aggregation without perturbing the conformational properties of tau monomers." J Mol Biol 426(8) 1736-1752 (2014) *Indicates equal contribution.
14. Yuzwa SA*, Shan X*, Macauley MS, Clark T, Skorobogatko Y, Vosseller K and Vocadlo DJ. "Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation." Nat Chem. Biol. 8 (4) 393-399 (2012) *Indicates equal contribution.
15. Yuzwa SA, Yadav AK, Skorobogatko Y, Clark T, Vosseller K, Vocadlo DJ. "Mapping O-GlcNAc modification sites on tau and generation of a site-specific O-GlcNAc tau antibody. Amino Acids 40 (3) 857-868 (2011).
16. Yuzwa SA, Macauley MS, Heinonen JE, Shan X, Dennis RJ, Yuan He, Whitworth GE, Stubbs KA, McEachern EJ, Davies GJ and Vocadlo DJ. "A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of Tau in vivo." Nat Chem. Biol. 4, 483-490 (2008).
Lab Mission Statement
To make important contributions to understanding the mechanisms of cell genesis in the developing and mature brain and to leverage these contributions, whenever possible, to impact human health.
Commitment to Diversity & Inclusion
It is my strong belief that the lab environment should be welcoming and inclusive for all members and I am committed to fostering that culture. We are all coming from different backgrounds with different lived experiences. This is not only the case with respect to our personal but also our scientific experiences. It is the union of everyone’s expertise and experiences that will make our lab a truly great place to work and learn. In the end, the more we can come together as a team and foster a collegial environment for everyone the more we will be able to achieve together to push the boundaries of the science we do! To succeed in my lab requires the ability to work with and support your peers, to engage in fun scientific discussions, to share in successes and hard times and to aim to be the best lab citizen possible.
I have been lucky enough to have some great mentors in my career and have seen just how valuable that can be. I take mentorship very seriously and aspire to be the best mentor I can be for each member of the lab. My goal is to model an adaptive approach for my trainees. Some incoming lab members with little experience need closer supervision and those already skilled in research need more independence. I tailor my approach for each individual and adjust as they gain experience and confidence in the lab. I hope that by modelling this approach, trainees will also learn how to become skilled mentors themselves and apply these skills within the lab and in their future careers.
With every member that joins the lab I make a point of discussing expectations. Both my expectations of you but also your expectations of me. This is important because I want everyone to enjoy their experience in the lab. Depending on your career stage, whether you’re an undergrad or a senior post-doc, the expectations will be different. Whatever your career stage I ask that you work hard, with the highest level of integrity and ethics, and do the best, rigorous, well designed experiments you can do. I prefer to set achievable goals together and then monitor progress towards those goals instead of focusing on hours worked when and where. It’s up to you to decide what that looks like. Ultimately, the more you put into your experiments the more you will get out of the research experience.
We are incredibly thankful to all of the funding agencies, below, who support our work!