Biography:

Dr. Freda Miller is a cell and molecular developmental neurobiologist at the Hospital for Sick Children Research Institute, Professor at University of Toronto. She is the Canada Research Chair in Developmental Neurobiology, a Howard Hughes Medical Institute International Research Scholar, a Fellow of the Royal Society of Canada, and the Secretary-Elect of the American Society for Neurosciences. Dr. Miller has authored more than 100 scientific papers, reviews and book chapters and has 15 patents (issued and pending). Dr. Miller is best known for her studies of neural stem cells and of neuronal growth, survival and apoptosis. Major findings from her lab have provided evidence that adult mammalian skin contains a multipotent neural crest-related stem cell that can be isolated and purified, that the p75 neurotrophin receptor is apoptotic and plays a growth inhibitory role in neurons, and that the p53 family members, p73 and p63 play a critical role in determining the life versus death of mammalian neurons. Dr. Miller has also patented methods for isolating dermal stem cells, and systems for studying neuronal life, growth, and death. Dr. Miller obtained her PhD in Medical Sciences from the University of Calgary and completed her postdoctoral research at the Scripps Research Foundation with Drs. F.E. Bloom and R.J. Milner. She then held faculty positions at the University of Alberta and the Montreal Neurological Institute at McGill University prior to moving to her current position in 2002. Dr. Miller is also a founder of Aegera Therapeutics Inc., a Canadian biotechnology companies.

Short summary of research interests:

During embryonic development, the mammalian nervous system is confronted with a problem of enormous complexity: to progress from a thin sheet of neuroepithelial stem cells to a network of neuronal connectivity that is able to process sensory information and generate an appropriate motor output. One way the nervous system achieves this end point is to overproduce neurons and neuronal connections and then eliminate the cells and connections that are not appropriate, a process that is not limited to the developing nervous system. Many of the same cellular mechanisms remain "in place" in adult animals, allowing structural and functional remodeling in response to physiological stimuli and providing repair mechanisms for the injured or degenerating 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 growth factors in the neural environment (1) regulate the genesis of neural cell types from embryonic neural stem cells and (2) determine neuronal survival, growth, and ultimately connectivity. In addition, we hope that the lessons we learn from studying neural development can be used to understand and potentially repair nervous system diseases and injury. With regard to the latter goal, one approach we have taken is to identify and characterize stem cells that have neural potential. We therefore focus on two populations of stem cells, the embryonic neural stem cells that build the developing brain, and a population of adult stem cells we have identified within mammalian dermis that show some neural potential.

With regard to embryonic neural stem cells, we have focused upon precursors within the developing cerebral cortex, where precursors generate neurons first and glia second. In this regard, our work has defined signaling pathways that regulate the genesis of these cell types from embryonic neural stem cells and has provided insight into the mechanisms that govern this sequential, timed cell genesis. More recently, our work has led us to ask whether genetic perturbations in these signaling pathways alter normal neural development and thus cause the cognitive or behavioral dysfunction found in certain genetic syndromes. In particular, we have hypothesized that perturbations in the timing and numbers of different neural cell types generated during embryogenesis have a profound impact on later developmental events such as neural circuit formation and ultimately neural function. We recently found at least one genetic disorder, Noonan syndrome, where this seems to be the case for the 30 to 50 percent of these individuals who have learning disabilities or mental retardation. In a mouse model of Noonan syndrome, the aberrant, genetically defined activation of the phosphatase SHP2, which underlies this syndrome, perturbs neural stem cell behavior, leading to inappropriate numbers of neurons versus glial cells. We hope that these types of studies will provide new ways to think about a group of devastating developmental disorders and will shed light on the normal and pathological development of the brain.

Adult stem cells have also attracted considerable interest because of their therapeutic potential and the insights they provide about the normal biology of adult mammalian tissues. We previously identified, isolated, and characterized SKPs, a population of multipotent adult stem cells that first appear in the dermis of rodents and humans during embryogenesis and persist into adulthood. We obtained evidence that SKPs represent an adult stem cell for the dermis, and we are currently testing this possibility by asking whether they are important for dermal maintenance and repair, for hair follicle formation, or for both. We also discovered that SKPs share properties with embryonic neural crest stem cells and are pursuing this finding in two ways. First, we are asking whether SKPs can generate the many and varied cell types that the neural crest produces during development. We now have evidence that these neural crest–related cells generate bona fide myelinating Schwann cells that not only myelinate an injured central nervous system (CNS) but also provide benefits in animal models of spinal cord injury. Second, we are asking whether human SKPs can be used as a general tool to study events that lead to human neural crest disease pathology. There are a large number of genetically defined neurocristopathies and peripheral neuropathies about which we know very little. We hope that, by generating SKPs from these human patients, we will be able to study the relevant neural crest–derived cell types at a molecular/cellular level and thus obtain novel insights into the pathology underlying these syndromes. We believe that these studies not only will shed light on the function, biology, and potential therapeutic utility of one type of adult stem cell, but also may ultimately provide important insights into a group of genetic disorders that are currently poorly understood.


Selected Recent References

Singh K.K., Park K.J., Hong E.J., Kramer B.M., Greenberg M.E., Kaplan D.R., and Miller F.D. Developmental axon pruning mediated by BDNF:p75NTR-dependent axon degeneration. Nat. Neurosci. 11, 649-658 (2008).

Wetzel M.K., Laliberte C.L., Biernaskie J.A., Cole C.J., Lerch J.P., Spring S., Wang S.-H., Henkelman R.M., Josselyn S.A., Frankland P.W., Miller F.D. and Kaplan D.R. p73 haploinsufficiency causes age-related neurodegeneration and aberrant tau filament formation. Neuron 11, 708-721 (2008).

Gauthier A.S, Furstoss O., Araki T., Chan R., Neel B., Kaplan D.R., and Miller F.D. Control of CNS cell fate decisions by SHP-2 and its dysregulation in Noonan syndrome. Neuron 54, 245-262 (2007).

Biernaskie J.A., Sparling J.S., Liu J., Shannon C.P., Plemel J.R., Xie R., Miller F.D. and Tetzlaff W. SKPs generate myelinating Schwann cells that promote myelination and functional recovery following contusion spinal cord injury. J. Neurosci. 27, 9545-9559 (2007).

Barnabe-Heider, F., Wasylnka, J.A., Fernandes K.J.L., Porsche C., Sendtner M., Kaplan, D.R. and Miller, F.D. Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin-1. Neuron 48, 253-265 (2005).

Fernandes, K.J.L., McKenzie, I., Mill, P., Akhavan, M., Smith, K., Barnabe-Heider, F., Kobayashi, N.R., Toma, J.G., Labosky, P.A., Kaplan, D.R., Hui, C-C. and Miller, F.D. An endogenous dermal niche for multipotent adult skin-derived precursor cells. Nat. Cell Biol. 6, 1082-1093 (2004).