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MacDonald Lab


Mechanisms of eye development and disease

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MacDonald Lab


Mechanisms of eye development and disease

Research

The overarching research aim of my laboratory is to understand how a healthy eye is built and maintained throughout life. More specifically, we are interested in how glial cells, the major support cells in the nervous system, are patterned and shaped during development to support neurons. We are also interested in what happens when the intricate glia-neuronal relationship breaks down due to increasing age or disease.

The retina is the light sensitive part of the eye that allows you to see. We use the zebrafish retina as a model as it contains the same neuron types and glial cells as the human eye. The zebrafish embryo is an incredible system to study development – it is transparent, we can label each cell with specific fluorescent markers and use time-lapse confocal microscopy to watch eye development happen in real time in a living fish! In addition to imaging we use CRISPR/Cas9 mutagenesis, RNA-sequencing and molecular biology to uncover and explore fundamental mechanisms of glial biology.

We are now interested in determining the cellular and molecular mechanisms regulating glial morphogenesis, with a particular focus on the consequences of disrupted glial contacts on neuronal function.


View our images and movies using the links to our galleries below.

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People


People


Current members


Former Members

The Sheffield Crew:

Dr. Aaron Savage
Ms. Emma White
Ms. Saskia Wyville

 

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Publications


Publications


Our Covers

Publications

Chhabria K, Vouros A, Gray C, MacDonald RB, Wilkinson RW, Plant K, Vasilaki E, Howarth C, Chico TJA. 2019. Sodium nitroprusside prevents the detrimental effects of glucose on the neurovascular unit and behaviour in zebrafish. Accepted in Disease Models & Mechanisms. bioRxiv http://dx.doi.org/10.1101/576942.

Kugler EC, van Lessen M, Daetwyler S, Chhabria K, Savage AM, Silva V, Plant K, MacDonald RB, Huisken J, Wilkinson RN, Schulte-Merker S, Armitage P, Chico TJA. 2019. Cerebrovascular endothelial cells form transient Notch-dependent cystic structures in zebrafish. EMBO Rep. 20:e47047. https://doi.org/10.15252/embr.201847047.

Charlton-Perkins M, Almeida AA, MacDonald RB* and Harris WA*. 2019. Genetic control of cellular morphogenesis in Müller glia. Glia. https://doi.org/10.1002/glia.23615.*Co-senior corresponding author. § Cover Article.

 Savage AM, Kurusamy S, Chen Y, Jiang Z, Chhabria K, Kim HR, Wilson HL, MacDonald RB, van Eeden FJM, Armesilla AL, Chico TJA, Wilkinson RN. 2019. tmem33 is essential for VEGF-mediated endothelial calcium oscillations and angiogenesis. Nature Comms. 10:732. https://doi.org/10.1038/s41467-019-08590-7

 Martins, RR, Ellis. PS, MacDonald RB, Richardson RJ, Henriques, CM. 2019. Resident immunity in tissue repair and maintenance: the zebrafish model coming of age. Front. Cell Dev. Biol. doi: https://doi.org/10.3389/fcell.2019.00012.

 Bergmann K, Santoscoy PM, Lygdas K, Nikolaeva Y, MacDonald RB*, Cunliffe V*, and Nikolaev A*. 2018. Imaging Neuronal Activity in the Optic Tectum of Late Stage Larval Zebrafish. J. Dev. Biol. 6(1);6-20. *Co-corresponding authors.

 MacDonald RB, Charlton-Perkins M and Harris WA. 2017. Mechanisms of Müller glial cell morphogenesis. Curr. Opin. Neurobiol. 47: 31-37. §Cover Article.

 MacDonald RB*, Kashikar N, Lagnado L and Harris WA. 2017. A novel transgenic zebrafish to measure extracellular glutamate in the nervous system. Zebrafish. 14(3): 284-286. * Corresponding Author. §Cover Article.

 Bivik C, MacDonald RB, Gunnar E, Mazouni K, Schweisguth F, and Thor S. 2016. Global Programmed Daughter Cell Proliferation Switch Controlled by Multi-layered Notch Signaling. PLoS Genetics. 12(4):e1005984.

 MacDonald RB, Randlett OR, Oswald J, Yoshimatsu T, Franze K, and Harris WA. 2015. Müller glial cells provide essential tensile strength to the developing retina. Journal of Cell Biology. 210(7): 1075-1083. §Cover article. *Highlighted in the JCB Special Issue 2016.

 Boije H, MacDonald RB and Harris WA. 2014. Reconciling competence and transcriptional hierarchies with stochasticity in retinal lineages. Curr. Opin. Neurobiol. 27C: 68-74.

 Baumgardt M*, Karlsson D*, Salmani BY, Bivik C, MacDonald RB and Thor S. 2014. The Temporal Gene Cascade Controls Daughter Cell Proliferation Mode Via G1 Cell Cycle Regulators. Developmental Cell. 30(2): 192-208.  

 MacDonald RB*, Pollack J*, Debiais-Thibaud M, Talbot JC and Ekker M. 2013. A conserved gene regulatory network controls the differentiation of GABAergic interneurons in the zebrafish prethalamus. Developmental Biology. 1606(13): 297-302. *Denotes equal contribution

 MacDonald RB*, Randlett OR*, Yoshimitsu T, Almeida AA, Suzuki SC, Wong RO and Harris WA. 2013. Cellular requirements for building a retinal neuropil. Cell Reports. 3(2): 282-290. *Denotes equal contribution. §Cover article. F1000 Exceptional Interest.

 Ulkvo C, MacDonald RB, Bivik C, Baumgardt M, Karlsson D, and Thor S. 2012. Control of neural lineage topology by a Notch-mediated switch in neural progenitor division mode. Development. 139(4): 678-89.

 Yu M, Xi Y, Pollack J, Debiais-Thibaud M, MacDonald RB, and Ekker M. 2011. Activity of dlx5a/dlx6a regulatory elements during zebrafish GABAergic neuron development. International Journal of Developmental Neuroscience. 29(7): 681-691.

 MacDonald RB, Debiais-Thibaud M, Talbot JC, and 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, Venkatesh B, and Ekker M. 2010. Functional conservation of a forebrain enhancer from the elephant shark (Callorhinchus milii) in zebrafish and mice. BMC Evolutionary Biology. 10:157.

 MacDonald RB, Debiais-Thibaud M, and Ekker M. 2010. Regulation of dlx gene expression in the zebrafish pharyngeal arches: from conserved enhancer sequences to conserved activity. Journal of Applied Ichthyology. 26(2): 187-191.

 Poitras L, Yu M, Lesage-Pelletier C, MacDonald RB, Gagné JP, Hatch G, Kelly I, Hamilton SP, Rubenstein JLR, Poirier GG and Ekker M. 2010. A SNP in an ultraconserved regulatory element affects Dlx5/Dlx6 regulation in the forebrain. Development. 137(18): 3089-3097.

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Image wall


Image wall


The star of the show: In the retina the principal glial type are the Müller glia (blue). These cells are elaborately shaped to contact neurons (yellow) and provide them with support so they function properly. I want to know how these glial cells get their shape in development. Optical section through the intact zebrafish retina with a Zeiss airyscan confocal. Genotype Tg(Tp1:Venus;ptf1a:dsRED).

In the mature retina Müller glia cells “tile” to make an elaborate non-overlapping support network for neurons. Each Müller glia cell is morphologically specialised at each layer of the retina and will establish its’ own unique spatial domain during development. Optical section through the intact zebrafish retina with a Zeiss Airyscan confocal. Genotype Tg(Tp1:Venus) and false coloured in FIJI.

The inner plexiform layer is the major synaptic neurpil of the retina. In this layer Müller glia cell (multi-coloured) sends elaborate projections to contact and support neuronal synapses. Genotype  Tg(Tp1:Venus)  and false coloured in FIJI.

The inner plexiform layer is the major synaptic neurpil of the retina. In this layer Müller glia cell (multi-coloured) sends elaborate projections to contact and support neuronal synapses. Genotype Tg(Tp1:Venus) and false coloured in FIJI.

We are trying to push the limits of our imaging to understand glial cells. This is a semi-super resolution reconstruction of Müller glia cells (green) and two different classes of amacrine cells (magenta and red) that will come together to make distinct synapses in the inner plexiform layer. Cryosection of the zebrafish retina taken on a Leica Sp8 and processed with Lightning software.

We are trying to push the limits of our imaging to understand glial cells. This is a semi-super resolution reconstruction of Müller glia cells (green) and two different classes of amacrine cells (magenta and red) that will come together to make distinct synapses in the inner plexiform layer. Cryosection of the zebrafish retina taken on a Leica Sp8 and processed with Lightning software.

The retina connects to the visual centres in the brain. Cryosection of the zebrafish brain and staining with DAPI (blue), phalloidin (red), HuC/D (neurons; magenta) and GFP (green). Genotype is Tg(NBT-GCaMP3) which labels neurons in the retina and tectum.

As the zebrafish retina matures glial cells must support the tissue to maintain healthy neurons and their connections or synapses. Cryosection of the adult zebrafish retina and staining with DAPI (blue), phalloidin (red), zpr3 (photoreceptors; magenta) and ribeye (synapses; green).

Müller glia express specific proteins that allow them to carry out their support functions in the retina. Cryosection of the zebrafish retina and immunohistochemistry for glutamine synthetase (magenta).

Müller glia are specifically labelled in the transgenic background  Tg(gfap:gfp).  We can use transgenic zebrafish or antibodies to specifically label and identify the glia or neurons in the retina. Cryosection of the zebrafish retina and immunohistochemistry for GFP.

Müller glia are specifically labelled in the transgenic background Tg(gfap:gfp). We can use transgenic zebrafish or antibodies to specifically label and identify the glia or neurons in the retina. Cryosection of the zebrafish retina and immunohistochemistry for GFP.

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Join us/Contact


Join us/Contact


Join us

We’re amazed by glia development and hope you are too. If you would like to join us please get in touch. We enthusiastically encourage applications from prospective students or postdocs. To see examples of our previous work please see the images and publications sections on the website or look us up on Instagram!

 

 

Our lab is part of several excellent graduate programmes:

Wellcome Trust/MRC PhD Programme in Neuroscience
UCL-Birkbeck MRC Doctoral Training Programme
• London Interdisciplinary Doctoral Programme

Please contact Ryan MacDonald more information.


Contact

Lab Address
MacDonald Lab
Institute of Ophthalmology
11-43 Bath St,
London EC1V 9EL
UK

(https://goo.gl/maps/j9BbfXv64rqYUJiF8) 

 

Email: ryan.macdonald@ucl.ac.uk
Twitter: MacDonald_Lab
Instagram: macdonald_lab

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Funding


Funding


 Our work is generously supported by the following funders: