Above: 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.

Above: 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).

Above: The various major cell types in the zebrafish retina.

Above: A cell dividing in the zebrafish retina

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? 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 Giuseppe Lupo (Postdoctoral Fellow)
Dr Daniel Maurus (Postdoctoral Fellow)
Dr Michalis Agathocleous (Postdoctoral Fellow)
Dr Caren Norden (Postdoctoral Fellow)
Dr Patricis Jusuf (Postdoctoral Fellow)

Mr Louis Leung (Graduate Student)
Miss Yan Xue (Graduate Student)
Miss Grace Wong (Graduate Student)
Mr Owen Randlett (Graduate Student)

Main Collaborators:
Christine Holt (PDN)
Dr Muriel Perron (CNRS)
Anna Philpott (Oncology)
Monica Vetter (University of Utah)
Sinichi Ohnuma (Oncology)
Steve Wilson (Kings College London)
Richard Adams (PDN)
Kate Lewis (PDN)
Ichiro Massai (RIKEN Inst, Japan)
Roger Pedersen (Surgery)
Stephen Eglen (Computational Biol)
Herwig Baier (UCSF)

Main sources of funding: Wellcome Trust.

Selected publications:

Agathocleous, M and Harris, WA (2009) From progenitors to differentiated cells in the vertebrate retina. Annu Rev Cell Dev Biol. (in press)

Norden, C, Young, S, Link, BA and Harris, WA (2009) Actomyosin is the main driver of interkinetic nuclear migration in the retina. Cell (in press)

Maurus D, Harris WA. (2009) Zic-associated holoprosencephaly: zebrafish Zic1 controls midline formation and forebrain patterning by regulating Nodal, Hedgehog, and retinoic acid signaling. Genes Dev. 23:1461-73.

Vitorino M, Jusuf PR, Maurus D, Kimura Y, Higashijima S, Harris WA. (2009) Vsx2 in the zebrafish retina: restricted lineages through derepression. Neural Dev. 4:14.

Zolessi FR, Poggi L, Wilkinson CJ, Chien CB, Harris WA. (2006) Polarization and orientation of retinal ganglion cells in vivo. Neural Dev.1:2.

Locker M, Agathocleous M, Amato MA, Parain K, Harris WA, Perron M. (2006) Hedgehog signaling and the retina: insights into the mechanisms controlling the proliferative properties of neural precursors. Genes Dev. 20:3036-48.

Van Raay, T.J., Moore, K.B., Iordanova, I., Steele, M., Jamrich, M., Harris, W.A. and Vetter, ML (2005) Frizzled 5 signaling governs the neural potential of progenitors in the developing Xenopus retina. Neuron 46:23-36.

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