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Professor William A Harris FMedSci FRS

We study the development of the nervous system using the retina of zebrafish and Xenopus as model systems. We seek to understand mechanisms that regulate cell proliferation, cell type specification and early neuronal patterning and differentiation.
Professor William A Harris, FMedSci FRS

Head of Department


Office Phone: +44 (0) 1223 333772, Fax: +44 (0) 1223 333786

Research Interests

Where does the nervous system come from in the embryo? How does it grow to the right size and shape? How do stem cells turn into more committed neuronal progenitors and how do these cells know when to leave the cycle and differentiate into neural and glial progenitors? How do particular regions of the nervous system produce the right number of neurons and the right proportions of the different types of neurons? Once born, how do these precursors differentiate? How do they choose a particular cell type to become amongst a myriad of possible fates, and by what cellular mechanisms do these cells become properly polarised, branched, and integrated into the retinal circuitry? What mechanisms allow retinal ganglion cells to send out long axons that forge pathways to their targets in the brain, and recognise specific cells within these targets?

The visual systems of Xenopus and zebrafish are ideal for such questions because of their embryological, molecular and genetic accessibility to experimentation, combined with the possibility of in vivo time-lapse imaging. The retina is an excellent system to explore the issue of cellular proliferation and diversity. We are unravelling some of the lineage dependent and lineage independent events that are used to push or induce cells to transition from proliferating retinal stem cells to differentiated neurons and glia particular fates and testing a variety of hypotheses concerning the mechanisms of fate specification and histogenesis. We are using similar approaches to investigate the mechanisms involved in the initial morphogenesis of various retinal neuron types. We are also conducting a variety of experiments on how the growing axons gather and transduce the information that allows them to find their way to their targets, exploring the machinery and the dynamics of growth cones at a molecular level.

Colleagues

Dr Xana Almeida (Postdoctoral Fellow)
Dr Mark Charlton-Perkins (Postdoctoral Fellow)

Dr Helena Khaliullina

Ms Megan Eldred

Mr Afnan Azizi

 

Main collaborators

Christine Holt (PDN)
Richard Adams (PDN)

Kristian Franze (PDN)

Anna Philpott (Oncology)
Ben Simons (Physics)
Jochen Guck (Physics)

Muriel Perron (CNRS)
Monica Vetter (University of Utah)
Steve Wilson (Kings College London)
Michalis Agathocleous (Univesity of Michigan)
Caren Norden (MPI Dresden)
Giuseppe Lupo (University of Rome)
Patricia Jusuf (University of Melbourne)

Ryan MacDonald (University of Sheffield)
Lucia Poggi (University of Heidelberg)
Michel Cayouette (IRCM Montreal)
Rachel Wong (University of Washington)

Teaching

Pt IB NST Neurobiology; Pt IB MVST NAB/HNB; Pt II NST N1; Pt II NST Mod P6/L6; Graduate CDBC

Key Publications

Goodings L, He J, Wood AJ, Harris WA, Currie PD, Jusuf PR. In vivo expression
of Nurr1/Nr4a2a in developing retinal amacrine subtypes in zebrafish
Tg(nr4a2a:eGFP) transgenics. J Comp Neurol. 2017 Jun 1;525(8):1962-1979. doi:
10.1002/cne.24185. Epub 2017 Mar 15. PubMed PMID: 28177524.


Eldred MK, Charlton-Perkins M, Muresan L, Harris WA. Self-organising
aggregates of zebrafish retinal cells for investigating mechanisms of neural
lamination. Development. 2017 Mar 15;144(6):1097-1106. doi: 10.1242/dev.142760.
Epub 2017 Feb 7. PubMed PMID: 28174240; PubMed Central PMCID: PMC5358108.


MacDonald RB, Kashikar ND, Lagnado L, Harris WA. A Novel Tool to Measure
Extracellular Glutamate in the Zebrafish Nervous System In Vivo. Zebrafish. 2016
Dec 27. doi: 10.1089/zeb.2016.1385. [Epub ahead of print] PubMed PMID: 28027028.


Hörnberg H, Cioni JM, Harris WA, Holt CE. Hermes Regulates Axon Sorting in the
Optic Tract by Post-Trancriptional Regulation of Neuropilin 1. J Neurosci. 2016
Dec 14;36(50):12697-12706. Epub 2016 Nov 9. PubMed PMID: 27974617; PubMed Central
PMCID: PMC5157111.


Khaliullina H, Love NK, Harris WA. Nutrient-Deprived Retinal Progenitors
Proliferate in Response to Hypoxia: Interaction of the HIF-1 and mTOR Pathway. J
Dev Biol. 2016 Jun;4(2). pii: 17. Epub 2016 May 19. PubMed PMID: 27280081; PubMed
Central PMCID: PMC4894462.


Wan Y, Almeida AD, Rulands S, Chalour N, Muresan L, Wu Y, Simons BD, He J,
Harris WA. The ciliary marginal zone of the zebrafish retina: clonal and
time-lapse analysis of a continuously growing tissue. Development. 2016 Apr
1;143(7):1099-107. doi: 10.1242/dev.133314. Epub 2016 Feb 18. PubMed PMID:
26893352; PubMed Central PMCID: PMC4852496.


Leung LC, Harris WA, Holt CE, Piper M. NF-Protocadherin Regulates Retinal
Ganglion Cell Axon Behaviour in the Developing Visual System. PLoS One. 2015 Oct
21;10(10):e0141290. doi: 10.1371/journal.pone.0141290. eCollection 2015. PubMed
PMID: 26489017; PubMed Central PMCID: PMC4619323.


MacDonald RB, Randlett O, Oswald J, Yoshimatsu T, Franze K, Harris WA. Müller
glia provide essential tensile strength to the developing retina. J Cell Biol.
2015 Sep 28;210(7):1075-83. doi: 10.1083/jcb.201503115. PubMed PMID: 26416961;
PubMed Central PMCID: PMC4586739.


Bertacchi M, Lupo G, Pandolfini L, Casarosa S, D'Onofrio M, Pedersen RA,
Harris WA, Cremisi F. Activin/Nodal Signaling Supports Retinal Progenitor
Specification in a Narrow Time Window during Pluripotent Stem Cell Neuralization.
Stem Cell Reports. 2015 Oct 13;5(4):532-45. doi: 10.1016/j.stemcr.2015.08.011.
Epub 2015 Sep 17. PubMed PMID: 26388287; PubMed Central PMCID: PMC4624997.


Boije H, Rulands S, Dudczig S, Simons BD, Harris WA. The Independent
Probabilistic Firing of Transcription Factors: A Paradigm for Clonal Variability
in the Zebrafish Retina. Dev Cell. 2015 Sep 14;34(5):532-43. doi:
10.1016/j.devcel.2015.08.011. Epub 2015 Sep 3. PubMed PMID: 26343455; PubMed
Central PMCID: PMC4572358.

 

Chow RW, Almeida AD, Randlett O, Norden C, Harris WA (2015), Inhibitory neuron migration and IPL formation in the developing zebrafish retina, Development, Aug 1;142(15):2665-77. PubMed PMID: 26116662

Almeida AD, Boije H, Chow RW, He J, Tham J, Suzuki SC, Harris WA (2014), Spectrum of Fates: a new approach to the study of the developing zebrafish retina, Development May;141(9):1971-80. PubMed PMID: 24718991

Randlett O, MacDonald RB, Yoshimatsu T, Almeida AD, Suzuki SC, Wong RO, Harris WA, (2013), Cellular requirements for building a retinal neuropil, Cell Rep. 3:282-90

He J, Zhang G, Almeida AD, Cayouette M, Simons BD, Harris WA, (2012), How variable clones build an invariant retina, Neuron, 75:786-98 PubMed PMID:22958820

Agathocleous M, Love NK, Randlett O, Harris JJ, Liu J, Murray AJ, Harris WA, (2012), Metabolic differentiation in the embryonic retina, Nat Cell Biol, 14:859-64

Randlett O, Poggi L, Zolessi FR, Harris WA, (2011), The oriented emergence of axons from retinal ganglion cells is directed by laminin contact in vivo, Neuron, 70:266-8

Norden C, Young S, Link BA, Harris WA, (2009), Actomyosin is the main driver of interkinetic nuclear migration in the retina, Cell, Sep 18;138(6):1195-208. PubMed PMID:19766571

Agathocleous M, Harris WA (2009), From progenitors to differentiated cells in the vertebrate retina, Annu Rev Cell Dev Biol. 25:45-69. PubMed PMID:19575661

Poggi L, Vitorino M, Masai I, Harris WA (2005), Influences on neural lineage and mode of division in the zebrafish retina in vivo, J Cell Biol, Dec 19;171(6):991-9. PubMed PMID:16365165

Zuber ME, Gestri G, Viczian AS, Barsacchi G, Harris WA, (2003), Specification of the  vertebrate eye by a network of eye field transcription factors, Development, Nov;130(21):5155-67. PubMed PMID:12944429

Ohnuma S, Philpott A, Wang K, Holt CE, Harris WA, (1999), p27Xic1, a Cdk inhibitor, promotes the determination of glial cells in Xenopus retina, Cell, Nov24;99(5):499-510. PubMed PMID:10589678

Zuber ME, Perron M, Philpott A, Bang A, Harris WA, (1999), Giant eyes in Xenopus laevis by overexpression of XOptx2, Cell, Aug 6;98(3):341-52. PubMed PMID:10458609

Above: Zebrafish retina showing Muller cells in purple and green.  Recent work from the lab shows that these cells provide mechanical resilience to the retina.

Above: Artistic impression of a young zebrafish retina with different types and subtypes of cells expressing differently coloured flourescent proteins (See Spectrum of Fates: a new approach to the study of the developing zebrafish retina, Almeida AD, Boije H, Chow RW, He J, Tham J, Suzuki SC, Harris WA, Development, May; 141(9):1971-80)

Above: Zebrafish retina showing on and off bipolar cells in purple and yellow. (see Cellular requirements for building a retinal neuropil, Randlett O, MacDonald RB, Yoshimatsu T, Almeida AD, Suzuki SC, Wong RO, Harris WA, Cell Rep.Feb 21;3(2):282-90)