Dr. Ryan MacDonald, PhD
JG Graves Medical Research Fellow
Department of Infection, Immunity & Cardiovascular Disease
University of Sheffield
Beech Hill Road
Room C03 Firth Court
University of Sheffield
2016 - present: Research Fellow, University of Sheffield, UK
2011 - 2016: Research Associate, University of Cambridge, UK
2010 - 2011: Postdoctoral Fellow, Linköping University, Sweden
2005 - 2010: PhD Student, University of Ottawa, Canada
2001 - 2005: BSc (Hons), University of New Brunswick, Canada
I have recently joined the University of Sheffield Medical School and Bateson Centre as a JG Graves Medical Research Fellow. My research career began as a PhD student at the University of Ottawa in Canada, under the supervision of Dr. Marc Ekker. It was in his laboratory that I first used the zebrafish as a model organism to study gene regulatory networks controlling the specification of GABAergic interneurons in the brain. After my PhD I was keen to continue studying neural specification, as such I took up a postdoc looking at Drosophila neurogenesis with Professor Stefan Thor in Sweden. Taking my knowledge of genetics and gene regulation I joined the laboratory of Professor Bill Harris at the University of Cambridge. It was in Cambridge where I learned to use the zebrafish retina to study neural development. In the Harris laboratory I explored glial specification and the consequences of glial loss on neuronal function and structure. I am now interested in the highly coordinated patterning of glial cells in the embryonic nervous system and how this changes after damage or disease.
Proper function of the nervous system requires the co-ordinated activity of neurons, which transmit electrical signals, microglia which provide immune functions and glia that provide a myriad of support functions. To perform these support functions glial cells need to take on the appropriate shapes and positions within the brain amongst neurons and synapses. However, we know very little about how glial cells are patterned during development. Glial cells are often the first responders to damage within the nervous system and alterations of their morphology results in a loss of neural support leading to neural degeneration. Additionally, microglia and endogenous glial cells work together to clear cellular debris from the extracellular space and maintain homeostasis. Breakdown in these interactions also plays a role in neural degeneration. Thus, defining the molecular and functional events that mediate effective neuron-glia and glia-glia interactions during development and disease is essential to fully understand these conditions.
To study these processes, I use the zebrafish retina as a model. The fish retina contains the same neuron types and glial cells as the human eye. The retina is made up of relatively simple neural circuits containing one type of endogenous glial cell, Müller glia (MG), and migrating microglia. MG and microglia perform all the functions necessary for support of the retinal neurons. MG cells have a very unique morphology in the retina and contact every neuron in the tissue. MG are patterned through highly dynamic interactions between other glial cells, however the molecular mechanisms controlling these events remain unknown. To study glial patterning in the developing retina we use CRISPR mutagenesis, RNA-sequencing, transgenesis with fluorescent reporters and time-lapse in vivo imaging. I hope to uncover the developmental mechanisms controlling glial patterning in the nervous system and determine their role in neurodegenerative disease.
Around one million people in the UK suffer from dementia, a typical manifestation of neurodegenerative disease, costing the health care system billions of pounds per year. Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration or death of nerve cells called neurons (e.g. Alzheimer's disease, Parkinson's disease, etc). Glial cells are the support cells for neurons and have a shape that is critical for these functions. I aim to understand how glial cells get their shape, how glia interact to support neurons and how this relationship breaks down during disease. I use the zebrafish to understand human disease because they share many biological processes with humans. Also, zebrafish embryos are transparent so we can observe how cells develop and behave in a living fish using specialised microscopes. I will use advanced genetic techniques to identify and test specific genes involvement in these dynamic cell behaviours with the goal to maintain glial shape and support after damage, thereby protecting neurons. My work will ultimately allow us to identify new drug targets to slow, or even cure, the devastating effects of neurodegenerative diseases.
Use of zebrafish in biomedical research, developmental biology, neuroscience.
- Associate Fellow of The Higher Education Academy (AFHEA).
- Clare Hall College Research Fellow, University of Cambridge.
- Free of the Company – The Worshipful Company of Spectacle Makers.
- Regulatory networks controlling glial patterning during development.
- Elucidating the pathways leading to gliosis after trauma or disease.
- Molecular mechanisms of glia-microglia interactions.
For key publications see below. For a full list of publications click here.
- MacDonald RB, Charlton-Perkins M & Harris WA (2017) Mechanisms of Müller glial cell morphogenesis. Current Opinion in Neurobiology, 47, 31-37.
- MacDonald RB, Kashikar ND, Lagnado L & Harris WA (2017) A Novel Tool to Measure Extracellular Glutamate in the Zebrafish Nervous System In Vivo. Zebrafish. View this article in WRRO
- Bivik C, MacDonald RB, Gunnar E, Mazouni K, Schweisguth F & Thor S (2016) Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling.. PLoS Genetics, 12(4). View this article in WRRO
- MacDonald RB, Randlett O, Oswald J, Yoshimatsu T, Franze K & Harris WA (2015) Müller glia provide essential tensile strength to the developing retina. Journal of Cell Biology, 210(7), 1075-1083. View this article in WRRO
- Boije H, MacDonald RB & Harris WA (2014) Reconciling competence and transcriptional hierarchies with stochasticity in retinal lineages. Current Opinion in Neurobiology, 27, 68-74. View this article in WRRO
- Baumgardt M, Karlsson D, Salmani BY, Bivik C, MacDonald RB, Gunnar E & Thor S (2014) Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade. Developmental Cell, 30(2), 192-208.
- MacDonald RB, Pollack JN, Debiais-Thibaud M, Heude E, Coffin Talbot J & Ekker M (2013) The ascl1a and dlx genes have a regulatory role in the development of GABAergic interneurons in the zebrafish diencephalon. Developmental Biology, 381(1), 276-285.
- Randlett O, MacDonald RB, Yoshimatsu T, Almeida AD, Suzuki SC, Wong RO & Harris WA (2013) Cellular Requirements for Building a Retinal Neuropil. Cell Reports, 3(2), 282-290.
- Ulvklo C, MacDonald R, Bivik C, Baumgardt M, Karlsson D & Thor S (2012) Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression. Development, 139(4), 678-689.
- Poitras L, Yu M, Lesage-Pelletier C, MacDonald RB, Gagne J-P, Hatch G, Kelly I, Hamilton SP, Rubenstein JLR, Poirier GG & Ekker M (2010) An SNP in an ultraconserved regulatory element affects Dlx5/Dlx6 regulation in the forebrain. Development, 137(18), 3089-3097.
- MacDonald RB, Debiais-Thibaud M, Talbot JC & Ekker M (2010) The relationship between dlx and gad1 expression indicates highly conserved genetic pathways in the zebrafish forebrain. Developmental Dynamics, 239(8), 2298-2306.
- MacDonald RB, Debiais-Thibaud M, Martin K, Poitras L, Tay BH, Venkatesh B & Ekker M (2010) Functional conservation of a forebrain enhancer from the elephant shark (Callorhinchus milii ) in zebrafish and mice.. BMC Evolutionary Biology, 10. View this article in WRRO