associated with astrocytes expressing VEGF mRNA. VEGF mRNA is also associated with the ganglion cell layer. These findings raise the possibility that in the incipient fovea, the ganglion cells are hypoxic, suggesting that the foveal depression could be an adaptation of the neural retina to a limited blood supply.

It is not well understood how the relationship between the perifoveal capillaries and the foveal depression is established. Taking a new approach to the problem of the formation of the foveal pit, Springer et al (2004). used virtual engineering models to identify mechanical mechanisms that could contribute to its formation [324]. Their data suggest that the foveal pit emerges as a consequence of the avascular zone. The absence of blood vessels makes the tissue within the avascular zone more elastic and malleable than the surrounding vascularized retina. Their models predict that the pit is formed because an absence of vasculature makes the inner retinal tissue of the avascular zone deformable.

As mentioned above, a characteristic of the fovea is the dense packing and elongation of photoreceptors in the central area. The mechanism responsible for these structural features is largely unknown. Any model would have to provide an explanation how rod photoreceptors are excluded from the fovea, and what triggers and maintains the high cone density. Cones are among the first retinal cells to become postmitotic at a particular location, and rods are among the last. The histogenesis of the retina follows a spatiotemporal gradient with the more central region differentiating into a laminated structure ahead of the more peripheral parts. As a result of the above considerations, the foveal cones are there among the first retinal cells to differentiate closely following the central ganglion and horizontal cells. Interestingly, when the central cones first differentiate at 11–12 weeks gestational age, they are relatively large, cuboidal in shape (~7 mm soma diameter), and arranged in a regular array with a spatial density of 14,200 cell/ mm2. By 24 weeks gestation, the density increases to 38,000 cones/mm2, and the soma diameter reduces to 4 mm. The process is indeed protracted as the final density of 100,000–324,000 cones/mm2 in humans is not reached until between 3 and 4 years of life [325]. This accumulation of foveal cones appears to occur in the absence of local cell divisions [313, 326]. As the above changes occur, the overall area of the foveolar cone mosaic contracts. The overall area of the mosaic is about 5 times greater during early development than in the adult [312, 325]. The available data suggest that the

accumulation of cones in the central retina arises through their displacement toward the foveolar cone mosaic (reviewed in [317]). The mechanism for the exclusion of rods from the fovea is also unclear. One explanation is that by the time significant numbers of rods are being generated during development, the incipient fovea has become overcrowded with cones physically excluding rods due to limited space. An alternative more attractive model is that specific factors inhibit the generation of rods in the fovea. This idea is consistent with the finding that foveal cones are present in the foveal photoreceptor mosaic early in development [319].

In summary, the fovea is a marvel of development. We are only just beginning to obtain a glimpse into the mechanisms responsible for its formation. The factors and molecular signaling pathways orchestrating the development of this remarkable structure have yet to be uncovered. Our understanding of the histogenesis ofthefoveaisthereforefarfromcomplete.Nevertheless, the critical importance of this specialized region for optimal resolving power and its vulnerability in conditions such as age-related macular degeneration provide compelling reasons to give more attention to uncovering the mystery of its development.

1.10  Nature and Books belong to the eyes that see them7

Our understanding of the embryology of the retina has come from diverse experimental systems ranging from drosophila to mice. The field illustrates how new ­techniques combined with clear thinking, hypothesisdriven research, long hours in the laboratory, and good colleagues can persuade the retina to reveal her secrets. Notwithstanding the significant advances in the field, there is the danger that we might conclude that everything important has already been found out, and everything significant is already known. However, as we enter the postgenome era, the main central questions regarding the mechanisms responsible for the development of the retina, and the patho­physiology of its diseases, appear as yet surprisingly unresolved!

Particularly exciting is the availability of new ­systems that provide a marriage between the classic embryological approaches and modern genetic

7Ralph Waldo Emerson (1803–1882)

technical strategies. For example, only a few years ago, the amphibian retina, which has proved so useful in classical embryological studies, was found to be very amenable to genetic manipulations (Figs. 1.20 and 1.21). The future is bright for this and other novel experimental approaches. We are therefore entering a new era where understandings from ocular embryology will have even more of the center stage in understanding the pediatric retina in both health and disease.

Reviewing what is known about the development of the retina is a humbling experience. We can only conclude­ that so little is really understood about the obvious important key questions. Of course, the reader should come away with an understanding of the significant­ contributions that others have made. More importantly, we should appreciate that the truly important insights and discoveries still await inquisitive minds.

Fig. 1.20  A young metamorphosed transgenic Nieuwkoop– Faber stage 66 Xenopus laevis (left) compared to a nontransgenic animal of the same age (right). The animals were photographed under white light in (a). (b) Shows fluorescence from green fluorescent protein (GFP) expressed in the photoreceptors of the transgenic animal (arrow). The fluorescence appears to be coming from the lens, but is actually originating from the retina behind it. Amphibians, such as Xenopus, provide important model systems to study ocular development. This is due to the feasibility of performing microdissections, and organ-

culture studies in these animals. Such manipulations are feasible because each cell is supported by an intercellular food droplet. The embryo does not require placenta or yoke sack, and is therefore accessible at all developmental stages. Their retinas are organized in a manner similar to our own, and the large size of the retinal neurons facilitate cellular studies. Finally, recent technical advances have allowed routine preparation of transgenic Xenopus allowing genetic strategies to be added to the experimental biologist’s tool chest. The images in this figure represent unpublished data from the author’s laboratory

Fig. 1.21  Confocal fluorescence photomicrographs of stage 35 Xenopus retina. (a) The expression of green fluorescent protein (GFP) is directed to developing photoreceptors using the rod opsin promoter. GFP fluorescence provides a way to visualize the cells recognizing the opsin promoter (generous gift of Dr. Barry E. Knox). Indirect immunofluorescence is used to localize rod opsin to the developing rod outer segments (secondary antibody is labeled with Texas Red) (arrowheads). (b) Higher magnification of the GFP expressing cells. Arrows, lipid droplets; asterisk, nonGFP expressing cone photoreceptors; bracket, region of cell containing nucleus. Further information regarding the use of Xenopus as an experimental system, contacts, and the government initiatives to stimulate this important field may be found at www.nih. gov/science/models/xenopus/index.html. The images in this figure represent unpublished data from the author’s laboratory

Acknowledgements  We extend an apology to the authors of the many excellent papers that could not be cited directly because of space constraints. Dr Gonzalez-Fernandez holds the Ira G. Olmsted Ross and Elizabeth P. Ross Chair of Ophthalmic Pathology. The Work was supported in part by Merit Review Award I01BX007080 from the Biomedical Laboratory Research & Development Service of the Veterans Affairs Office of Research and Development, RO1 EY09412, R24 EY016662 core instrumentation grant, and an unrestricted grant from Research to Prevent Blindness.

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