Saturday, 23rd June 2018

Development and regeneration

    Cellular and molecular bases of vertebrate eye morphogenesis




Florencia Cavodeassi




Research summary:

Cellular and molecular bases of vertebrate eye morphogenesis

Group Leader: Florencia Cavodeassi

Our eyes are in fact part of our brain, and this is most obvious early in embryonic development, when the primordia of the eyes arise as outgrowths from the forming brain. Our group is interested in understanding how does a subset of brain cells become destined to form the eyes, and in dissecting the mechanisms driving the complex cellular movements that shape the mature eyes. These questions are actually very important, since defects during early stages of eye development result in congenital malformations and are amongst the most severe defects associated with blindness. For this purpose we exploit the many advantages of the zebrafish as a model system to analyse morphogenetic processes and model human diseases.

The acquisition of eye identity by a group of cells in the primordium of the brain is followed by their segregation from the surrounding cells fated to become brain. Susequently eye cells rearrange in space to give rise to the optic vesicles, the primordia of the eyes. As the optic vesicles evaginate, eye cells polarise, elongate and intercalate radially among each other, in a morphogenetic process that we propose promotes the lateral expansion of the optic primordia. Some of our most recent work has identified part of the molecular mcehanisms involved in controlling these events.

The evaginating optic vesicles become gradually partitioned in smaller subdomains, with different cellular identities. These two processes (morphogenesis and patterning of the eye primordium) have to be tightly coordinated to give rise to a mature, functional organ. Our latest studies, in collaboration with the group of Steve Wilson at UCL (London, UK) address this issue, and have already led us to show that the first stage in this patterning process occurs at the onset of optic vesicle evagination and requires the coordinated function of the Hedgehog (Hh) and Fibroblast-growth-factor (Fgf) signalling pathways. We are currently extending these studies to determine how the role of Hh and Fgfs in promoting regional fates in the optic primordium is coordinated with the dynamic cell rearrangements observed during optic vesicle evagination, by monitoring eye fate acquisition in vivo.

Once the optic vesicles are formed, they undergo further morphogenesis to give rise to the optic cups. As this transition takes place they become subdivided into retina an retinal pigmented epithelium (RPE). The retina constitutes a laminar structure formed by a discrete number of neuronal types, from which the photoreceptors are the responsible to receive the visual stimuli. The RPE is a thin, pigmented epithelium that covers the retina and provides trophic support to the photoreceptors. In the zebrafish, the first morphological manifestation of retina versus RPE fate is the transition of the RPE from a pseudostratified epithelium to a thin monolayer of cells. As they change shape, RPE cells spread over the back of the folding optic cup. This change in cell shape is thought to provide a rigid scaffold against which the prospective retina folds. The mechanisms controlling the change of shape of RPE cells, however, have been poorly explored. In a collaborative effort with Paola Bovolenta, we aim to determine the sequence of morphogenetic events involved in RPE morphogenesis and the impact of this process on optic cup folding. For this purpose we have generated transgenic tools that are allowing us to undertake a dynamic analysis of the changes in RPE cell shape and organisation that accompany optic cup folding.

Schematic of the brain at neural plate, optic vesicle and early optic cup stage. Modified from Picker et al., 2009.



Frontal view of the evaginating eye field (labelled by Tg {rx3:GFP} expression, red) prior (11.5hpf, A), during (12.5hpf, B) and after (13.5hpf, C) evagination, showing gradual polarisation of the tissue as evagination proceeds. The apical domain of the cells is highlighted in green by immunostaining with antibodies to ZO-1 (A,B) and aPKC (C).








Selected publications:


María Hernández-Bejarano, Gaia Gestri, Lana Spawls, Francisco Nieto-López, Alexander Picker, Masa Tada, Michael Brand, Paola Bovolenta, Stephen W. Wilson*, and Florencia Cavodeassi* (2015).Opposing Shh and Fgf signals initiate nasotemporal patterning of the retina. Development, vol. 142: 3933-3942. *Corresponding author.

Kenzo Ivanovitch, Florencia Cavodeassi* and Steve Wilson* (2013). Precocious acquisition of neuroepithelial character in the eye field underlies the onset of eye morphogenesis. Developmental Cell, vol. 27: 293-305. *Corresponding author.

Florencia Cavodeassi*, Kenzo Ivanovitch and Steve Wilson* (2013). Eph/Ephrin signalling maintains eye field segregation from adjacent neural plate territories during forebrain morphogenesis. Development, vol. 140: 4193-202. *Corresponding author.

Alexander Picker, Florencia Cavodeassi, Anja Machate, Sabine Bernauer, Stefan Hans, Gembu Abe, Koichi Kawakami, Stephen W. Wilson and Michael Brand (2009). Dynamic Coupling of Pattern Formation and Morphogenesis in the Developing Vertebrate Retina. PLoS Biology, vol. 7: e1000214.

Florencia Cavodeassi, Filipa Carreira-Barbosa, Rodrigo M. Young, Miguel L. Concha, Miguel L. Allende, Corinne Houart, Masazumi Tada and Stephen W. Wilson (2005). Early stages of zebrafish eye formation require the coordinated activity of Wnt11, Fz5 and the Wnt/ß-catenin pathway. Neuron, vol. 47: 43-56.