The mechanism of deep foveal pit formation is not yet known. It is possible that these changes are related to the completion of the ring of vasculature around the fovea. The pit becomes progressively deeper and more pronounced through the rest of fetal development and early childhood. The length of the cone axons continues to increase, and the cell bodies become thinner (Fig. 5). The final adult cone density peaks at more than 200,000 cones/mm2 [2, 26, 28, 99].

There has been considerable debate concerning the mechanism of pit formation. This is because it is difficult to test the hypotheses since an animal model has not been available that has a foveal pit and is easily manipulated during retinal development. A recent model for foveal pit formation was proposed by Springer and Hendrickson and based on morphological observations in the developing human retina [100]. They applied a virtual engineering model combined with finite element analysis to identify mechanical mechanisms important for pit formation. They hypothesized that the pit emerges within the foveal region because it contains an avascular zone, which makes this region more elastic compared to surrounding vascularized retina (Fig. 4 E,F, arrowheads). The conclusion from their modeling study is that once differential elasticity is established by the avascular zone, pit formation and a concomitant increase in cone density can be driven by either intraocular pressure or ocular growth-induced retinal stretch.

Foveal Hypoplasia

The long developmental time frame of foveal development allows for numerous points where mutations or missteps can occur. These mistakes or defects can lead to foveal hypoplasia, a condition in which an individual lacks a foveal pit, avascular zone, and rod-free zone [41]. Foveal hypoplasia results in decreased vision with reduced acuity (6/24 to 6/120 or 20/80 to 20/400 [41, 101]). The underlying cause of foveal hypoplasia is not yet known, although it has been associated with many eye conditions, including albinism, microcornea, familial and presenile cataracts, and PAX6 mutations [38, 39, 44].

The degree of hypoplasia is likely correlated with the gene defect. For example, it has been suggested that PAX6 is associated with the specification of foveal location. If foveal location is not established (step 1), then the correct microenvironment for setting up the rod-free zone and pit formation will be missing, thus halting development at an early time point. In the case of albinism, the central retina is lacking a rod-free zone, which suggests that this step is critical to stimulate a fovea [41]. It may be that the presence of vasculature across the foveal region also inhibits pit formation. Taken together, the characteristics of foveal hypoplasia suggest that interruption of any of the steps outlined in this chapter will cause moderate-to-severe central retinal malformations that have a profound effect on functional vision (Fig. 6).

CONCLUSIONS AND PERSPECTIVES

Changes in the foveal cone photoreceptors and the progression of primate foveal pit formation are summarized in Figs. 5 and 6. These figures show the progression of the different steps of foveal development in relation to major cellular movements and developmental events. Step 1 is initiated very early in retinal development (approximately fetal week 3). Once the location is specified, the correct cellular environment must be

Fig. 6. Summary of the stages of foveal development. The steps in foveal development are outlined with reference to the change in cone density, developmental age, and important morphological events. Fwk fetal week OD optic disk (Modified from [104].)

specified during the second step, which is completed by fetal week 11. Step 3 slowly increases the density of cones via signaling molecules such as the FGFs (Figs. 5 and 6). Step 3 is completed around fetal week 32. Once the avascular ring is completed around birth, there is a sharp rise in the density of cones and a concomitant increase in cone length and decrease in cone diameter (Figs. 5 and 6). The mature fovea is apparent at approximately 4 years of age [2, 26].

When the structure of the human foveal pit is compared to the deep foveal pits of fish, birds, and lizards, it is difficult to imagine that they are formed by a similar mechanism. For example, one of the requirements of the virtual engineering model is the presence of an avascular zone. As none of these animal models has retinal vasculature, any forces proposed to be acting on the avacular zone to form a deep pit would be missing. Therefore, step 4 may not be required for the formation of all foveae, but this restriction does not have to be placed on the other preceding three steps when investigating a mechanism for early foveal development in nonprimates. There may be a universal mechanism in place to carry out the initial steps in foveal formation, such as in step 1, the specification of location. All of the observed foveal pits are faithfully located in a particular retinal location, indicating that the placement of the fovea at the center of gaze is an important step in the formation of the fovea. The development of the rod-free zone (step 2) also appears to be a generally conserved foveal requirement. The majority of foveae studied have a clearly defined rod-free zone in the fovea [6–8, 102, 103]. An increased cone density (step 3) appears to be a common feature in the center of foveal pits. This suggests that it is possible that the mechanisms that function early in foveal development are conserved among species to create a rod-free, cone-rich foveal pit, but that the formation of either a deep, steep foveal pit or a wide, shallow pit (primates) is dependent on divergent mechanisms. The argument concerning the evolution of the fovea can be summarized in the question: Is there can be an evolutionarily conserved mechanism to create the foveal pit in all these creatures, or does the distant relation of the primates, birds, and lizards

require that a completely separate mechanism exist? Likely, the answer lies somewhere in the middle.

The primate fovea can be characterized by the modification of retinal lamination, specialization of photoreceptors, and variation of the retinal vascular pattern. All of these characteristics combine to mediate our high visual acuity. The development of the fovea begins early in fetal development and continues until at least 4 years of age. When the four steps outlined in this chapter are faithfully reproduced, a characteristic fovea is formed (Figs. 1B and 5). Future research will help to elucidate the mechanisms by which the foveal specialization is formed with the hope of recapitulating these events in congenitally malformed or diseased retinae.

ACKNOWLEDGMENTS

I would like to thank Drs. Jan Provis, Dorothea Schulte, and Anita Hendrickson for valuable discussions of this topic. A special thanks is extended to Dr. Provis for her critical reading of the manuscript. Research in my labs is supported by the Center for Vision Excellence, the University of Auckland Staff Research Fund, and the Auckland Medical Research Foundation.

REFERENCES

1.Polyak S. The retina. Chicago: University of Chicago Press; 1941.

2.Hendrickson AE, Yuodelis C. The morphological development of the human fovea. Ophthalmology 1984;91;603–612.

3.Curcio CA, et al. Distribution and morphology of human cone photoreceptors stained with anti-blue opsin. J Comp Neurol 1991;312;610–624.

4.Robinson,S.Developmentofthemammalianretina.In:DreherB,RobinsonS,eds.Neuroanatomy of the visual pathways and their development. Boca Raton, FL: CRC Press; 1991:69–128.

5.Collin SP, Collin HB. Topographic analysis of the retinal ganglion cell layer and optic nerve in the sandlance Limnichthyes fasciatus (Creeiidae, Perciformes). J Comp Neurol 1988;278:226–241.

6.Collin SP, Collin HB. The morphology of the retina and lens of the sandlance, Limnichthyes fasciatus (Creeiidae). Exp Biol 1988;47:209–218.

7.Collin SP, Collin HB. The foveal photoreceptor mosaic in the pipefish, Corythoichthyes paxtoni (Syngnathidae, Teleostei). Histol Histopathol 1999;14:369–382.

8.Collin SP, Lloyd DJ, Wagner HJ. Foveate vision in deep-sea teleosts: a comparison of primary visual and olfactory inputs. Philos Trans R Soc Lond B Biol Sci 2000;355:1315–1320.

9.Fritsches KA, Marshall NJ. Independent and conjugate eye movements during optokinesis in teleost fish. J Exp Biol 2002;205:1241–1252.

10.Walls GL. The vertebrate eye and its adaptive radiation. Bloomfield Hills, MI: Cranbrook Institute of Science; 1942.

11.Kirk EC, Kay RF. The evolution of high visual acuity in the Anthropoidea. In: Ross CF, Kay RF, eds. Anthropoid origins: new visions, New York: Kluwer /Plenum; 2004:539–602.

12.Boire D, Dufour JS, Theoret H, Ptito M. Quantitative analysis of the retinal ganglion cell layer in the ostrich, Struthio camelus. Brain Behav Evol 2001;58:343–355.

13.Fite KV, Rosenfield-Wessels S. A comparative study of deep avian foveas. Brain Behav Evol 1975;12:97–115.

14.Hodos W, Miller RF, Fite KV. Age-dependent changes in visual acuity and retinal morphology in pigeons. Vision Res 1991;31:669–677.

15.Blough PM. The visual acuity of the pigeon for distant targets. J Exp Anal Behav 1971;15:57–67.

16.Hodos W, Leibowitz RW, Bonbright JC Jr. Near-field visual acuity of pigeons: effects of head location and stimulus luminance. J Exp Anal Behav 1976;25:129–141.

17.Reymond L. Spatial visual acuity of the eagle Aquila audax: a behavioural, optical and anatomical investigation. Vision Res 1985;25:1477–1491.

18.Osterberg G. Topography of the layer of rods and cones in the human retina. Acta Ophthal 1935;6:1–103.

19.Ahnelt PK, Kolb H, Pflug R. Identification of a subtype of cone photoreceptor, likely to be blue sensitive, in the human retina. J Comp Neurol 1987;255:18–34.

20.Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. Human photoreceptor topography. J Comp Neurol 1990;292:497–523.

21.Wikler KC, Williams RW, Rakic P. Photoreceptor mosaic: number and distribution of rods and cones in the rhesus monkey retina. J Comp Neurol 1990;297:499–508.

22.Diaz-Araya CM, Provis JM, Billson FA. NADPH-diaphorase histochemistry reveals cone distributions in adult human retinae. Aust N Z J Ophthalmol 1993;21:171–179.

23.Perry VH, Cowey A. The ganglion cell and cone distributions in the monkey’s retina: implications for central magnification factors. Vision Res 1985;25:1795–1810.

24.Packer O, Hendrickson AE, Curcio CA. Photoreceptor topography of the retina in the adult pigtail macaque (Macaca nemestrina). J Comp Neurol 1989;288:165–183.

25.Bumsted K, Hendrickson A. Distribution and development of short-wavelength cones differ between Macaca monkey and human fovea. J Comp Neurol 1999;403:502–516.

26.Yuodelis C, Hendrickson A. A qualitative and quantitative analysis of the human fovea during development. Vision Res 1986;26:847–855.

27.Bach L, Seefelder R. Entwicklungsgeschichte des Menchlichlichen Auges. Leipzig, 1911, 1912, 1914.

28.Mann, I. In: The development of the human eye. 2nd ed. New York: Grune and Stratton; 1964.

29.Dowling JE, Boycott BB. Retinal ganglion cells: a correlation of anatomical and physiological approaches. UCLA Forum Med Sci 1969;8:145–161.

30.Calkins DJ, Tsukamoto Y, Sterling P. Microcircuitry and mosaic of a blue-yellow ganglion cell in the primate retina. J Neurosci 1998;18:3373–3385.

31.Calkins DJ, Schein SJ, Tsukamoto Y, Sterling P. M and L cones in macaque fovea connect to midget ganglion cells by different numbers of excitatory synapses. Nature 1994;371:70–72.

32.Wassle H. Parallel processing in the mammalian retina. Nat Rev Neurosci 2004;5:747–757.

33.Ghosh KK, Goodchild AK, Sefton AE, Martin PR. Morphology of retinal ganglion cells in a new world monkey, the marmoset Callithrix jacchus. J Comp Neurol 1996;366:76–92.

34.Goodchild AK, Ghosh KK, Martin PR. Comparison of photoreceptor spatial density and ganglion cell morphology in the retina of human, macaque monkey, cat, and the marmoset Callithrix jacchus. J Comp Neurol 1996;366:55–75.

35.DeBruyn EJ, Wise VL, Casagrande VA. The size and topographic arrangement of retinal ganglion cells in the galago. Vision Res 1980;20:315–27.

36.Rohen JW, Castenholz A. [On the centralization of the retina in primates]. Folia Primatol (Basel) 1967;5:92–147.

37.Constable IJ. Age-related macular degeneration and its possible prevention. Despite well publicised claims of the therapeutic value of dietary supplements and other new treatments, the evidence for their effectiveness is modest. Med J Aust 2004;181:471–472.

38.Curran RE, Robb RM. Isolated foveal hypoplasia. Arch Ophthalmol 1976;94:48–50.

39.Oliver MD, Dotan SA, Chemke J, Abraham FA. Isolated foveal hypoplasia. Br J Ophthalmol 1987;71:926–930.

40.Haefemeyer JW, Knuth JL. Albinism. J Ophthalmic Nurs Technol 1991;10:55–62.

41.Mietz H, Green WR, Wolff SM, Abundo GP. Foveal hypoplasia in complete oculocutaneous albinism. A histopathologic study. Retina 1992;12:254–260.

42.Azuma N, Nishina S, Yanagisawa H, Okuyama T, Yamada M. PAX6 missense mutation in isolated foveal hypoplasia. Nat Genet 1996;13:141–142.

43.Meyer CH, Lapolice DJ, Freedman SF. Foveal hypoplasia in oculocutaneous albinism demonstrated by optical coherence tomography. Am J Ophthalmol 2002;133:409–410.

44.McGuire DE, Weinreb RN, Goldbaum MH. Foveal hypoplasia demonstrated in vivo with optical coherence tomography. Am J Ophthalmol 2003;135:112–114.

45.Vincent MC, et al. Variable phenotype related to a novel PAX 6 mutation (IVS4+5G>C) in a family presenting congenital nystagmus and foveal hypoplasia. Am J Ophthalmol 2004;138:1016–1021.

46.Pal B, et al. A new phenotype of recessively inherited foveal hypoplasia and anterior segment dysgenesis maps to a locus on chromosome 16q23.2–24.2. J Med Genet 2004;41:772–777.

47.Azuma N, et al. The Pax6 isoform bearing an alternative spliced exon promotes the development of the neural retinal structure. Hum Mol Genet 2005;14:735–745.

48.Williams TD, Wilkinson JM. Position of the fovea centralis with respect to the optic nerve head. Optom Vis Sci 1992;69:369–377.

49.Dutting D, Meyer SU. Transplantations of the chick eye anlage reveal an early determination of nasotemporal polarity. Int J Dev Biol 1995;39:921–931.

50.Dutting D, Thanos S. Early determination of nasal-temporal retinotopic specificity in the eye anlage of the chick embryo. Dev Biol 1995;167:263–281.

51.Thanos S, Dutting D. Plasticity in the developing chick visual system: topography and maintenance of experimentally induced ipsilateral projections. J Comp Neurol 1988;278:303–311.

52.Thanos S, Mey J, Dutting D, Hummler E. Positional determination of the naso-temporal retinal axis coincides with asymmetric expression of proteins along the anterior-posterior axis of the eye primordium. Exp Eye Res 1996;63:479–492.

53.Mueller BK, Dutting D, Haase A, Feucht A, Macchi P. Partial respecification of nasotemporal polarity in double-temporal chick and chimeric chick-quail eyes. Mech Dev 1998;74:15–28.

54.Peters MA. Patterning the neural retina. Curr Opin Neurobiol 2002;12:43–48.

55.Peters MA, Cepko CL. The dorsal-ventral axis of the neural retina is divided into multiple domains of restricted gene expression which exhibit features of lineage compartments. Dev Biol 2002;251:59–73.

56.Schulte D, Furukawa T, Peters MA, Kozak CA, Cepko CL. Misexpression of the Emx-related homeobox genes cVax and mVax2 ventralizes the retina and perturbs the retinotectal map. Neuron 1999;24:541–553.

57.Schulte D, Cepko CL. Two homeobox genes define the domain of EphA3 expression in the developing chick retina. Development 2000;127:5033–5045.

58.Logan M, Simon HG, Tabin C. Differential regulation of T-box and homeobox transcription factors suggests roles in controlling chick limb-type identity. Development 1998;125:2825–2835.

59.Uemonsa T, Sakagami K, Yasuda K, Araki M. Development of dorsal-ventral polarity in the optic vesicle and its presumptive role in eye morphogenesis as shown by embryonic transplantation and in ovo explant culturing. Dev Biol 2002;248:319.

60.Dutting D, Handwerker C, Drescher U. Topographic targeting and pathfinding errors of retinal axons following overexpression of ephrinA ligands on retinal ganglion cell axons. Dev Biol 1999;216:297–311.

61.Feldheim DA, et al. Loss-of-function analysis of EphA receptors in retinotectal mapping. J Neurosci 2004;24:2542–2550.

62.Zhang XM, Yang XJ. Temporal and spatial effects of Sonic hedgehog signaling in chick eye morphogenesis. Dev Biol 2001;233:271–290.

63.Li H, et al. A retinoic acid synthesizing enzyme in ventral retina and telencephalon of the embryonic mouse. Mech Dev 2000;95:283–289.

64.Niederreither K, Vermot J, Schuhbaur B, Chambon P, Dolle P. Retinoic acid synthesis and hindbrain patterning in the mouse embryo. Development 2000;127:75–85.

65.Suzuki R, et al. Identification of RALDH-3, a novel retinaldehyde dehydrogenase, expressed in the ventral region of the retina. Mech Dev 2000;98:37–50.

66.Zhao D, et al. Molecular identification of a major retinoic-acid-synthesizing enzyme, a retin- aldehyde-specific dehydrogenase. Eur J Biochem 1996;240:15–22.

67.Barbieri AM, et al. A homeobox gene, vax2, controls the patterning of the eye dorsoventral axis. Proc Natl Acad Sci U S A 1999;96:10729–10734.

68.Ohsaki K, Morimitsu T, Ishida Y, Kominami R, Takahashi N. Expression of the Vax family homeobox genes suggests multiple roles in eye development. Genes Cells 1999;4:267–276.

69.Shintani T, et al. Large-scale identification and characterization of genes with asymmetric expression patterns in the developing chick retina. J Neurobiol 2004;59:34–47.

70.Yuasa J, Hirano S, Yamagata M, Noda M. Visual projection map specified by topographic expression of transcription factors in the retina. Nature 1996;382:632–635.

71.Deitcher DL, Fekete DM, Cepko CL. Asymmetric expression of a novel homeobox gene in vertebrate sensory organs. J Neurosci 1994;14:486–498.

72.Schulte D, Peters MA, Sen J, Cepko CL. The rod photoreceptor pattern is set at the optic vesicle stage and requires spatially restricted cVax expression. J Neurosci 2005;25:2823–2831.

73.Belecky-Adams T, Adler R. Developmental expression patterns of bone morphogenetic proteins, receptors, and binding proteins in the chick retina. J Comp Neurol 2001;430:562–572.

74.Martinez-Morales JR, et al. Differentiation of the vertebrate retina is coordinated by an FGF signaling center. Dev Cell 2005;8:565–574.

75.Sakai Y, Luo T, McCaffery P, Hamada H, Drager UC. CYP26A1 and CYP26C1 cooperate in degrading retinoic acid within the equatorial retina during later eye development. Dev Biol 2004;276:143–157.

76.Sen J, Harpavat S, Peters MA, Cepko CL. Retinoic acid regulates the expression of dorsoventral topographic guidance molecules in the chick retina. Development 2005;132:5147–5159.

77.Adler R, Belecky-Adams TL. The role of bone morphogenetic proteins in the differentiation of the ventral optic cup. Development 2002;129:3161–3171.

78.Leconte L, Lecoin L, Martin P, Saule S. Pax6 interacts with cVax and Tbx5 to establish the dorsoventral boundary of the developing eye. J Biol Chem 2004;279:47272–47277.

79.Schmid KL, Wildsoet CF. Assessment of visual acuity and contrast sensitivity in the chick using an optokinetic nystagmus paradigm. Vision Res 1998;38:2629–2634.

80.Morris VB. An afoveate area centralis in the chick retina. J Comp Neurol 1982;210:198–203.

81.Barishak Y. Embryology of the eye and its adnexae. New York: Karger; 1992.

82.Hendrickson AE. Synaptic development in macaque monkey retina and its implications for other developmental sequences. Perspect Dev Neurobiol 1996;3:195–201.

83.Hendrickson AE. Primate foveal development: a microcosm of current questions in neurobiology. Invest Ophthalmol Vis Sci 1994;35:3129–3133.

84.Rapaport DH, Fletcher JT, LaVail MM, Rakic P. Genesis of neurons in the retinal ganglion cell layer of the monkey. J Comp Neurol 1992;322:577–588.

85.Provis JM, van Driel D, Billson FA, Russell P. Development of the human retina: patterns of cell distribution and redistribution in the ganglion cell layer. J Comp Neurol 1985;233:429–451.

86.Georges P, Madigan MC, Provis JM. Apoptosis during development of the human retina: relationship to foveal development and retinal synaptogenesis. J Comp Neurol 1999;413:198–208.

87.Penfold PL, Provis JM. Cell death in the development of the human retina: phagocytosis of pyknotic and apoptotic bodies by retinal cells. Graefes Arch Clin Exp Ophthalmol 1986;224:549–553.

88.Bumsted O’Brien K, Schulte D, Hendrickson A. Expression of photoreceptor-associated molecules during fetal human eye development. Mol Vis 2003;9:401–409.

89.Bumsted O’Brien KM, et al. Expression of photoreceptor-specific nuclear receptor NR2E3 in rod photoreceptors of fetal human retina. Invest Ophthalmol Vis Sci 2004;45:2807–2812.

90.Mears AJ, et al. Nrl is required for rod photoreceptor development. Nat Genet 2001;29: 447–452.

91.Hendrickson A, Provis JM. Comparison of development of the primate fovea centralis with peripheral retina. In: Sernagor E, Eglen S, Harris WA, Wong R, eds. Retinal development. Cambridge, UK: Cambridge University Press; 2006:126–149.

92.Diaz-Araya C, Provis JM. Evidence of photoreceptor migration during early foveal development: a quantitative analysis of human fetal retinae. Vis Neurosci 1992;8:505–514.

93.Cornish EE, et al. Gradients of cone differentiation and FGF expression during development of the foveal depression in macaque retina. Vis Neurosci 2005;22:447–459.

94.Cornish EE, Natoli RC, Hendrickson A, Provis JM. Differential distribution of fibroblast growth factor receptors (FGFRs) on foveal cones: FGFR-4 is an early marker of cone photoreceptors. Mol Vis 2004;10:1–14.

95.Springer AD, Hendrickson AE. Development of the primate area of high acuity, 3: temporal relationships between pit formation, retinal elongation and cone packing. Vis Neurosci 2005;22:171–185.

96.Provis JM, et al. Development of the human retinal vasculature: cellular relations and VEGF expression. Exp Eye Res 1997;65:555–568.

97.Gariano RF, Sage EH, Kaplan HJ, Hendrickson AE. Development of astrocytes and their relation to blood vessels in fetal monkey retina. Invest Ophthalmol Vis Sci 1996;37:2367–2375.

98.Gariano RF, Iruela-Arispe ML, Sage EH, Hendrickson AE. Immunohistochemical characterization of developing and mature primate retinal blood vessels. Invest Ophthalmol Vis Sci 1996;37:93–103.

99.Provis JM, Billson FA, Russell P. Ganglion cell topography in human fetal retinae. Invest Ophthalmol Vis Sci 1983;24:1316–1320.

100.Springer AD, Hendrickson AE. Development of the primate area of high acuity. 1. Use of finite element analysis models to identify mechanical variables affecting pit formation. Vis Neurosci 2004;21:53–62.

101.Health MO. Children with disabilities. In: English B, ed. Our children’s health: key findings on the health of New Zealand children. Wellington, NZ: Ministry of Health; 1998:51–65.

102.Collin SP. Specialisations of the teleost visual system: adaptive diversity from shallowwater to deep-sea. Acta Physiol Scand Suppl 1997;638:5–24.

103.Collin SP. Topography and morphology of retinal ganglion cells in the coral trout Plectropoma leopardus (Serranidae): a retrograde cobaltous-lysine study. J Comp Neurol 1989;281:143–158.

104.Provis JM, Penfold PL, Cornish EE, Sandercoe TM, Madigan MC. Anatomy and development of the macula: specialisation and the vulnerability to macular degeneration. Clin Exp Optom 2005;88:269–281.