ReviewPax6 lights-up the way for eye development
Introduction
Eye development in vertebrates has been an excellent model system to investigate fundamental processes in developmental biology from tissue induction to the formation of highly specialized structures such as the lens and the retina. This complex optic system develops primarily from three embryonic parts: the optic vesicle (OV), which is a lateral evagination from the wall of the diencephalon, the surrounding mesenchyme and the overlying surface ectoderm (SE). Successive signals between these tissue components are thought to coordinate their development (Fig. 1a). The OV contacts the SE and triggers a response that leads to a thickening of the ectoderm, the lens placode, which later develops into the mature lens. While the lens placode internalizes to form the lens vesicle, the distal OV invaginates to form the optic cup with the inner layer developing into the neuroretina (NR) and the outer layer forming the retinal pigmented epithelium (RPE). The proximal regions of the OV form the optic stalk that connects the retina to the brain.
Recently, the expression and function of numerous genes have been correlated with defined cell types and stages of eye development. Comparison of gene expression, function and regulation in development of the fly and vertebrate eyes has revealed a surprising conservation of molecular mechanisms. In particular, the study of the transcription factor Pax6 promoted our understanding of the development of ocular tissues. Pax6 is a member of the Pax family of transcription factors. It contains two DNA-binding motifs the paired domain and paired-type homeodomain [1]. In vertebrates this factor is essential for normal development of several organs including the brain, pancreas and the eye [2]. Pax6 has been reported to be a key regulator of eye development as it is both essential for eye formation in different organisms as well as sufficient to induce ectopic eyes in flies and frogs upon misexpression 3., 4•.. Interestingly, the correct dosage of Pax6 is essential for normal eye development: overexpression of Pax6 in mice results in a severe eye phenotype [5], whereas reduction of Pax6 activity in heterozygotes for Pax6 mutation results in ocular phenotypes such as Aniridia in humans [6] and Small eye in mice and rats 7., 8.. The conserved expression pattern of Pax6 in the developing and adult vertebrate eye and recent functional studies of Pax6 by conditional mutagenesis document the involvement of this factor in a whole spectrum of events essential for normal eye development.
In this review we highlight the recent results on the molecular mechanisms underlying the development of the eye as unraveled by the study of this gene. Readers are directed to recent comprehensive reviews for further discussion on evolution of eyes 9., 10. and on cell proliferation and differentiation in the retina [11].
Section snippets
Lens induction from experimental embryology to molecular mechanisms
The early, pioneering work of Spemann [12] described lens induction as a single step process in which the OV influences the development of the SE. Today, lens induction is conceived as a multi-step process (Fig. 1a) 13., 14.. The competence of the SE to respond to lens inductive signals is acquired during gastrulation. Subsequently, at the neural plate stage, planar signals from the adjacent neural folds further bias the ectoderm enhancing its lens-forming capacity. The expression pattern and
Pax6 in early lens development
Several findings document an essential role of Pax6 during early stages of lens induction: first, Pax6−/Pax6− cells are excluded from the SE of chimeric embryos [28], second, the expression of the lens-specification marker Sox2 fails in Pax6−/Pax6− embryos (Fig. 2d) 18., 29., and third, tissue recombination between OV and SE from Pax6−/Pax6− and wild-type rat embryos suggested that Pax6 is not essential for the inductive activity of the OV, but rather has a cell autonomous function in the SE
Pax6 in early retina development
The growing OV contains bipotential progenitors that could give rise to both RPE and NR cell types. Separation of these progenitors to NR and RPE domains is mediated by external cues. Fibroblast growth factors (FGFs) secreted from the SE promote NR cell fate, whereas the ocular mesenchyme directs RPE formation (Fig. 4a) 41., 42., 43•., 44•.. Finally, Sonic hedgehog (Shh) secreted from the ventral forebrain seems to influence the patterning of the OV [45•]. These early positional cues impose
Pax6 in retinal progenitors cells
The vertebrate retina is composed of six types of neurons and one type of glia, which are interconnected in a complex, highly ordered cytoarchitecture [53]. During retinogenesis the different retinal cell types are generated in a defined birth order from a population of multipotent retinal progenitor cells (RPCs) residing in the inner layer of the optic cup. Retinal ganglion cells, cone photoreceptors and horizontal cells are born first, followed by amacrine and rod photoreceptor cells, while
Conclusions
Recent studies have revealed that Pax6 mediates two sequential steps during early lens development: lens-bias and lens-specification. In contrast to the complete dependence of lens specification on Pax6 activity, during retinal development Pax6 function seems to be partly compensated by factors acting in parallel to confer retinal identity. The combined function of these factors probably confers the competence of RPC to differentiate into the different cell types. Further analysis of the role
Acknowledgments
We thank for discussions and comments on the manuscript Uri Ashery, Maria Belaoussoff, Kamal Chowdhury, Thomas Hollemann, Michael Kessel, Petros Petrou, Michal Reichman, Anastassia Stoykova, and especially Guy Goudreau and Till Marquardt for sharing unpublished observations and for valuable input, and Claus-Peter Adam for help with the illustrations. R Ashery-Padan was supported by a long-term EMBO fellowship. This research was supported by the Max Planck Society and the EU BIO4 CT 960042.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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