Big eyes/small eyes: identifying signals that regulate eye formation
Florencia Cavodeassi and Steve Wilson
Original paper reference
Cavodeassi, F., Carreira-Barbosa, F., Young, R.M, Concha, M.L., Allende, M.L., Houart, C., Tada, M. and Wilson, S.W. (2005).
Early stages of zebrafish eye formation require the coordinated activity of Wnt11, Fz5 and the Wnt/β-catenin pathway
You might not realise it but your eyes are in fact part of your brain. Early in embryonic development, the eyes arise as outgrowths from the forming brain. How does a subset of brain cells become destined to form the eyes and how do these cells then undergo the complex movements that must occur during eye formation? In this study, we addressed the role of genes functioning in the Wnt pathway, a cell-to-cell signalling pathway, in the regulation of early steps of eye formation.
The primordium of the mature eyes is specified as a single "eye-field" of cells at very early stages of embryonic development. At this stage, the nervous system is just a simple sheet of cells called the neural plate. As the neural plate folds up to form the brain, the eye-field splits in two and evaginates from the brain to form left and right eyes.
In zebrafish embryos, the eye field and other regions of the prospective brain can be readily visualised within the neural plate by the overlapping expression of various genes encoding transcription factors. The eye field is surrounded anteriorly by the prospective telencephalon, and posteriorly by the prospective diencephalon (Figure 1).
The Wnt signalling pathway has been well studied and work done by our group and others, suggested a model whereby a gradient of Wnt activity specifies different regional fates within the anterior neural plate. The model suggested high levels of Wnt activity specify diencephalic fates and lower levels of Wnts specify gradually more anterior fates, such as the eye field and the telencephalon. In this study, we re-examined the role of the Wnt pathway during eye field specification, and found that it is more complex than expected. Wnt proteins can activate several different signalling cascades: simplistically, Wnt/β-catenin signalling leads to changes in gene expression and the identity of cells (like brain versus eye) whereas Wnt/PCP signalling leads to changes in cell shape and movements.
By doing a series of experiments where we activated or switched off the Wnt pathway locally within the anterior neural plate, we found that these two branches of the pathway have very different effects on eye formation (Figure 2). High levels of Wnt/β-catenin signalling tells cells to become diencephalic brain and blocks eye formation. In contrast, Wnt/PCP activity within the eye field promotes eye formation, and it does so, at least partially, by antagonising the Wnt/β-catenin pathway. Each branch of the Wnt pathway appears to be activated by a different combination of Wnts and their receptors (called Fzs) in the nascent forebrain. Thus, Wnt8b and Fz8a activate the Wnt/β-catenin pathway, while Wnt11 and Fz5 activate the non-canonical pathway.
These results were surprising, and revealed an unexpected role for the Wnt/PCP pathway in promoting eye formation by locally antagonising Wnt/β-catenin signals that would otherwise block eye formation. In addition, our study further showed a requirement for Wnt/PCP signalling to regulate the behaviour and movements of the eye field cells, promoting their cohesion. This probably helps to ensure that the eye cells behave as a coherent group during the complex tissue movements that form the eyes. Thus, the Wnt/PCP pathway, activated by the interaction between Wnt11 and Fz5, seems to have a dual role during early stages of eye formation: it promotes eye field specification, and regulates the behaviour of the eye field cells. In doing so, the Wnt/PCP pathway is an essential coordinator of the early stages of eye formation.
Our work on this project was primarily funded by the Wellcome Trust and a Fellowship from the HFSP.