Research
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.
Publications
Shigeoka T, Koppers M, Wong HH, Lin JQ, Cagnetta R, Dwivedy A, de Freitas Nascimento J, van Tartwijk FW, Ströhl F, Cioni JM, Schaeffer J, Carrington M, Kaminski CF, Jung H, Harris WA, Holt CE. (2019) On-Site Ribosome Remodeling by Locally Synthesized Ribosomal Proteins in Axons. Cell Rep. 29:3605-3619..
Koppers M, Cagnetta R, Shigeoka T, Wunderlich LC, Vallejo-Ramirez P, Qiaojin Lin J, Zhao S, Jakobs MA, Dwivedy A, Minett MS, Bellon A, Kaminski CF, Harris WA, Flanagan JG, Holt CE. (2019) Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons. Elife. 8. pii: e48718.
Turner-Bridger B, Jakobs M, Muresan L, Wong HH, Franze K, Harris WA, Holt CE. (2018) Single-molecule analysis of endogenous β-actin mRNA trafficking reveals a mechanism for compartmentalized mRNA localization in axons. Proc Natl Acad Sci U S A. 115:E9697-E9706.
Cioni JM, Wong HH, Bressan D, Kodama L, Harris WA, Holt CE. (2018) Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function. Neuron. 97:1078-1093. item 288508209.
MacDonald RB, Charlton-Perkins M, Harris WA. (2017) Mechanisms of Müller glial cell morphogenesis. Curr Opin Neurobiol. 47:31-37.
Wong HH, Lin JQ, Ströhl F, Roque CG, Cioni JM, Cagnetta R, Turner-Bridger B, Laine RF, Harris WA, Kaminski CF, Holt CE. (2017) RNA Docking and Local Translation Regulate Site-Specific Axon Remodeling In Vivo. Neuron. 95:852-868.
Eldred MK, Muresan L, Harris WA. (2019) Disaggregation and Reaggregation of Zebrafish Retinal Cells for the Analysis of Neuronal Layering. Methods Mol Biol. 1576:255-271.
Khaliullina-Skultety H, Zi Chao N, Harris WA. (2017) Induction of Hypoxia in Living Frog and Zebrafish Embryos. J Vis Exp. 26;(124).
Goodings L, He J, Wood AJ, Harris WA, Currie PD, Jusuf PR. (2017) In vivo expression of Nurr1/Nr4a2a in developing retinal amacrine subtypes in zebrafish Tg(nr4a2a:eGFP) transgenics. J Comp Neurol. 525:1962-1979.
Eldred MK, Charlton-Perkins M, Muresan L, Harris WA. (2017) Self-organising aggregates of zebrafish retinal cells for investigating mechanisms of neural lamination. Development. 144:1097-1106.
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.
Hörnberg H, Cioni JM, Harris WA, Holt CE. (2016) Hermes Regulates Axon Sorting in the Optic Tract by Post-Trancriptional Regulation of Neuropilin 1. J Neurosci. 36:12697-12706.
Khaliullina H, Love NK, Harris WA. (2016) Nutrient-Deprived Retinal Progenitors Proliferate in Response to Hypoxia: Interaction of the HIF-1 and mTOR Pathway. J Dev Biol. 4(2).
Wan Y, Almeida AD, Rulands S, Chalour N, Muresan L, Wu Y, Simons BD, He J, Harris WA. (2016) The ciliary marginal zone of the zebrafish retina: clonal and time-lapse analysis of a continuously growing tissue. Development 143:1099-107.
Leung LC, Harris WA, Holt CE, Piper M. (2015) NF-Protocadherin Regulates Retinal Ganglion Cell Axon Behaviour in the Developing Visual System. PLoS One. 10(10):e0141290.
MacDonald RB, Randlett O, Oswald J, Yoshimatsu T, Franze K, Harris WA. (2016) Müller glia provide essential tensile strength to the developing retina. J Cell Biol. 210:1075-83.
Bertacchi M, Lupo G, Pandolfini L, Casarosa S, D'Onofrio M, Pedersen RA, Harris WA, Cremisi F. (2015) Activin/Nodal Signaling Supports Retinal Progenitor Specification in a Narrow Time Window during Pluripotent Stem Cell Neuralization.
Stem Cell Reports. 5:532-45.
Boije H, Rulands S, Dudczig S, Simons BD, Harris WA. (2015) The Independent Probabilistic Firing of Transcription Factors: A Paradigm for Clonal Variability in the Zebrafish Retina. Dev Cell. 34:532-43.
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
