Professor, Michael Smith Laboratories and Department of Medical Genetics, University of British Columbia
Affiliate Professor, School of Biomedical Engineering and Associate Member, ICORD, University of British Columbia
The overall current interests of the laboratory involve the tissue-specific precursor cells that build, maintain and repair mammalian tissues, with a particular focus on neural and mesenchymal precursor cells. With regard to the nervous system, during embryonic development the mammalian brain is confronted with a profoundly complex issue; to progress from a thin sheet of neuroepithelial cells to a network of neuronal circuitry that is able to process sensory information and generate an appropriate motor output. One of the ways that the mammalian nervous system achieves this end point is by overproducing both neurons and neuronal connections, and then eliminating those cells and/or connections that are not appropriate. However, this is not something that is limited to the developing nervous system. Many of the same cellular mechanisms remain “in place” in adult animals, thereby allowing structural and/or functional remodeling in response to physiological stimuli and providing repair mechanisms for the injured and traumatized mature nervous system. These complex developmental processes are determined by an intimate interplay between intrinsic cellular programs and environmental cues. Within this broad context, my laboratory is interested in understanding how environmental cues like growth factors regulate the genesis of developing neurons and glia and in so doing regulate the establishment of appropriate neuronal connectivity during normal and abnormal brain development. Moreover, we are interested in asking whether similar mechanisms are in play for the neural precursors that reside in the adult brain, and whether we can use this information to recruit those endogenous precursors to promote brain repair.
The second major question we are interested in are the mechanisms that underly the repair and regeneration of mesenchymal tissues. This work is based upon the increasing evidence indicating that tissue repair is mediated, at least in part, by endogenous tissue-derived adult stem cells. However, we still have limited knowledge about the molecular mechanisms that determine stem cell numbers and longevity and/or the environmental signals that promote stem cell maintenance while still allowing their differentiation under basal or pathological conditions. To address these questions we have focused on mesenchymal precursors and on skin repair and on one of the true examples of multi-tissue regeneration in adult mammals, the regenerating murine digit tip. It is our hope that by understanding normal mammalian regeneration, we can learn to promote repair and/or regeneration in the many situations where these do not normally occur.
Selected publications from the past 7 years
Borrett M.J., Innes B.T., Jeong D., Tahmasian N., Storer M.A., Bader G.D., Kaplan D.R., and Miller F.D. (2020). Single cell profiling shows that murine forebrain quiescent NSCs reacquire a developing precursor state when activated to make adult-born neurons. Cell Reports 32, 108022.
Ayoub R., Ruddy R., Cox E., Oyefiade A., Derkach D., Laughlin S., Ades-aron B., Shirzadi Z., Fieremans E., MacIntosh B., de Medeiros C., Skocic J., Bouffet E., Miller F.D., Morshead C.M. and Mabbot D.J. (2020). Assessment of cognitive and neural recover in survivors of pediatric brain tumors in a pilot clinical trial using metformin. Nat. Med. 26, 1285-1294.
Storer M.A., Mahmud N., Karamboulas K., Borrett M.J., Yuzwa S.A., Androschuk A., Sefton M.V., Kaplan D.R. and Miller F.D. (2020) Acquisition of a unique mesenchymal precursor-like blastema state underlies successful adult mammalian digit tip regeneration. Dev. Cell 52, 509-524.
Tomita H., Cornejo F., Aranda-Pino B., Woodard C.L., Rioseco C.C., Neel B.G., Alvarez A.R., Kaplan D.R., Miller F.D. and Cancino G.I. (2020) The protein tyrosine phosphatase receptor delta regulates developmental neurogenesis. Cell Reports, 30, 215-228.
Carr M.J., Toma J.S., Johnston A.P.W., Steadman P.E., Yuzwa S.A., Mahmud N., Frankland P.W., Kaplan D.R. and Miller F.D. (2019). Mesenchymal precursor cells in adult nerves contribute to mammalian tissue repair and regeneration. Cell Stem Cell 24, 240-256.
Zahr S.K., Yang G., Kazan H., Yuzwa S.A., Borrett M.J., Kaplan D.R. and Miller F.D. (2018). A translational repression complex in developing mammalian neural stem cells that regulates neuronal specification. Neuron 97, 520-537.
Storer M., Gallagher D., Fatt M.P., Simonetta J., Kaplan D.R. and Miller F.D. (2018). Interleukin-6 regulates adult neural stem cell numbers during normal and abnormal postnatal development. Stem Cell Reports 10, 1464-1480.
Yuzwa S.A., Borrett M.J., Innes B.T., Voronova A., Ketela T., Kaplan D.R., Bader G.D., and Miller F.D. (2017). Developmental emergence of adult neural stem cells as revealed by single cell transcriptional profiling. Cell Reports 21, 3970-3986.
Voronova A., Yuzwa S.A., Wang B., Zahr S., Syal C., Wang J., Kaplan D.R., and Miller F.D. (2017). Migrating interneurons secrete fractalkine to promote oligodendrocyte formation in the developing mammalian brain. Neuron, 94, 500-516.
Johnston A.P.W., Yuzwa S.A., Carr M.J., Mahmud N., Storer M.A., Krause M.P., Jones K., Paul S., Kaplan D.R., and Miller F.D. (2016). Dedifferentiated Schwann cell precursors secreting paracrine factors are required for regeneration of the mammalian digit tip. Cell Stem Cell 19, 433-448.
Yuzwa S.A., Yang G., Borrett M., Clarke G., Cancino G.I., Zahr S.K., Zandstra P.W., Kaplan D.R., and Miller F.D. (2016). Proneurogenic ligands defined by modeling developing cortex growth factor communication networks. Neuron 91, 988-1004.
Yang G., Cancino G.I., Zahr S.K., Guskjolen A., Voronova A., Gallagher D., Frankland P.W., Kaplan D.R., and Miller F.D. (2016). A Glo1-methylglyoxal pathway that is perturbed in maternal diabetes regulates embryonic and adult neural stem cell pools in murine offspring. Cell Reports 17, 1022-1036.
Gallagher D., Voronova A., Zander M.A., Cancino G.I., Bramall A., Krause M.P., Abad C., Tekin M., Neilsen P.M., Callen D.F., Scherer S.W., Keller G.M., Kaplan D.R., Walz K., and Miller F.D. (2015) Ankrd11 is an epigenetic regulator involved in autism that is essential for neural development. Dev. Cell 32, 31-42.
Amadei G., Zander M.A., Yang G., Dumelie J.G., Vessey J.P., Lipshitz H.D., Smibert C.A., Kaplan D.R., and Miller F.D. (2015). A Smaug2-based translational repression complex determines the balance between precursor maintenance versus differentiation during mammalian neurogenesis. J. Neurosci. 35, 15666-15681.
Yang, G., Smibert C.A., Kaplan, D.R., and Miller F.D. (2014). An eIF4E/4E-T complex determines the genesis of neurons from precursors by translationally repressing a proneurogenic transcription program. Neuron 84, 723-739.
Zander M.A., Burns S.E., Yang G., Kaplan D.R., and Miller F.D. (2014) Snail coordinately regulates conserved downstream pathways to control multiple aspects of mammalian neural precursor biology. J. Neurosci. 34, 5164-5175.
Gallagher D., Norman A.A., Woodard C.L., Yang G., Gauthier-Fisher A., Fujitani M., Vessey J.P., Cancino G.I., Sachewsky N., Woltjen K., Fatt M.P., Morshead C.M., Kaplan D.R., and Miller F.D. (2013) Transient maternal IL-6 mediates long-lasting changes in neural stem cell pools by deregulating an endogenous self-renewal pathway. Cell Stem Cell 13, 564-576.
Dr. Miller joins UBC from the Hospital for Sick Children in Toronto, where she was a Senior Scientist and Professor at the University of Toronto. She is a Fellow of the Royal Society of Canada and of the American Association for the Advancement of Science and at the Hospital for Sick Children she was a Howard Hughes Medical Institute International Research Scholar and the Canada Research Chair in Developmental Neurobiology. Most recently, Dr. Miller ‘s accomplishments were recognized by the naming of the “Dr. Freda Miller” public school by the Calgary Board of Education.
Dr. Miller is best known for her work on dermal and neural stem cells and on mechanisms that regulate neuronal survival and growth. Her discovery of dermal stem cells provided insights into the mechanisms underlying skin maintenance and repair and contributed to providing the conceptual basis for using skin as a major source for genesis of human stem cells. At the same time, Dr. Miller discovered new mechanisms determining whether nerve cells live or die, findings that have implications for our understanding of neurodegenerative disorders. Finally, Dr. Miller has made significant contributions to understanding how stem cells build the brain during normal development and how this goes awry in neurodevelopmental disorders. This led to her recent discovery that the commonly used diabetes drug metformin can recruit endogenous neural precursors and in so doing can promote repair of the injured brain.
These discoveries led to clinical trials for therapies that “wake up” our own stem cells to repair the injured brain and skin and to the co-founding of two biotechnology companies.