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EPSRC CDT in Sensor Technologies for a Healthy and Sustainable Future



Molecular Embryogenesis of the Visual System

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.

Above: How the brain is made. By combining advanced imaging with powerful genetic labelling techniques, Professor Bill Harris has imaged the entire process of retinal development in four dimensions, providing new insights into the enormous complexity of the nervous system.

 Successive frames from a time-lapse study of transgenically labelled cell dividing in the zebrafish retina, generating two daughter cells, one of which becomes a retinal ganglion cell (yellow).

A time-lapse series of the apical complex fusion protein (Par3-GFP) as retinal ganglion cell precursors exit the cell cycle and begin to differentiate. Par3-GFP starts at the apical surface of the neuroepithelium (top and bottom in this reflected image) and migrates basally with the detaching apical process of the retinal ganglion cell precursor as it transforms from a neuroepithelial shape towards a maturing neuronal morphology.



Key publications: 

Lupo G, Novorol C, Smith JR, Vallier L, Miranda E, Alexander M, Biagioni S, Pedersen RA, Harris WA. (2013) Multiple roles of Activin/Nodal, bone morphogenetic protein, fibroblast growth factor and Wnt/β-catenin signalling in the anterior neural patterning of adherent human embryonic stem cell cultures. Open Biol. 3:120167.

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.

Leung LC, Urbančič V, Baudet ML, Dwivedy A, Bayley TG, Lee AC, Harris WA, Holt CE. (2013) Coupling of NF-protocadherin signaling to axon guidance by cue-induced translation. Nat Neurosci. 16:166-73.

Kechad A, Jolicoeur C, Tufford A, Mattar P, Chow RW, Harris WA, Cayouette M. (2012) Numb is required for the production of terminal asymmetric cell divisions in the developing mouse retina. J Neurosci. 32:17197-210.

Jusuf PR, Albadri S, Paolini A, Currie PD, Argenton F, Higashijima S, Harris WA, Poggi L. (2012) Biasing amacrine subtypes in the Atoh7 lineage through expression of Barhl2. J Neurosci. 32:13929-44.

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

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.

Wong GK, Baudet ML, Norden C, Leung L, Harris WA (2012) Slit1b-Robo3 signaling and N-cadherin regulate apical process retraction in developing retinal ganglion cells. J Neurosci. 32:223-8.

Leung L, Klopper AV, Grill SW, Harris WA, Norden C (2011) Apical migration of nuclei during G2 is a prerequisite for all nuclear motion in zebrafish neuroepithelia. Development. 138:5003-13.

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. 70:266-80.

Jusuf PR, Almeida AD, Randlett O, Joubin K, Poggi L, Harris WA. (2011) Origin and determination of inhibitory cell lineages in the vertebrate retina. J Neurosci. 31:2549-62.

Gomes FL, Zhang G, Carbonell F, Correa JA, Harris WA, Simons BD, Cayouette M. (2011) Reconstruction of rat retinal progenitor cell lineages in vitro reveals a surprising degree of stochasticity in cell fate decisions. Development. 138:227-35.

Professor of Physiology, Development and Neuroscience
Professor Bill  Harris