Chapter Three - Eye Morphogenesis and Patterning of the Optic Vesicle

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Abstract

Organogenesis of the eye is a multistep process that starts with the formation of optic vesicles followed by invagination of the distal domain of the vesicles and the overlying lens placode resulting in morphogenesis of the optic cup. The late optic vesicle becomes patterned into distinct ocular tissues: the neural retina, retinal pigment epithelium (RPE), and optic stalk. Multiple congenital eye disorders, including anophthalmia or microphthalmia, aniridia, coloboma, and retinal dysplasia, stem from disruptions in embryonic eye development. Thus, it is critical to understand the mechanisms that lead to initial specification and differentiation of ocular tissues. An accumulating number of studies demonstrate that a complex interplay between inductive signals provided by tissue–tissue interactions and cell-intrinsic factors is critical to ensuring proper specification of ocular tissues as well as maintenance of RPE cell fate. While several of the extrinsic and intrinsic determinants have been identified, we are just at the beginning in understanding how these signals are integrated. In addition, we know very little about the actual output of these interactions. In this chapter, we provide an update of the mechanisms controlling the early steps of eye development in vertebrates, with emphasis on optic vesicle evagination, specification of neural retina and RPE at the optic vesicle stage, the process of invagination during morphogenesis of the optic cup, and maintenance of the RPE cell fate.

Introduction

The vertebrate eye is formed through coordinated interactions between neuroepithelium, surface ectoderm, and extraocular mesenchyme, which originates from two sources: neural crest and mesoderm. Following eye field formation, the neuroepithelium of the ventral forebrain evaginates, resulting in the formation of bilateral optic vesicles (Fig. 3.1A). The distal portion of the vesicle makes contact with the overlying surface ectoderm (lens ectoderm), which is then induced to form the lens placode. This interaction results in invagination of the lens placode and distal optic vesicle leading to formation of a bilayered optic cup (Fig. 3.1B). The neural retina develops from the inner layer of the optic cup, and the retinal pigment epithelium (RPE) is derived from the outer layer. The margin between the two layers gives rise to peripheral structures, the iris epithelium and ciliary body. The most proximal part of the optic vesicle, the optic stalk, “narrows” to become the optic fissure. The lens vesicle eventually separates from the surface ectoderm and differentiates into the mature lens. Tissue–tissue interactions, mediated by extracellular factors and intrinsic signals such as transcription factors, control differentiation of ocular tissues starting at the optic vesicle stage.

Much progress has been made in recent years elucidating the mechanisms involved in evagination and proximodistal patterning of the optic vesicle, and morphogenesis of the optic cup; therefore, these topics will be the focus of this chapter. The reader is referred to many excellent reviews for discussions of other aspects of early eye development, such as lens and optic stalk formation, dorsoventral and nasotemporal patterning of the optic vesicle, as well as differentiation of ciliary body and iris epithelium (Adler & Canto-Soler, 2007, Davis-Silberman & Ashery-Padan, 2008, Donner et al., 2006, Hyer, 2004, Lang, 2004, Morcillo et al., 2006, Takahashi et al., 2009, Yang, 2004, Zhao et al., 2010).

Section snippets

Evagination of the Optic Vesicles

The first morphological sign of eye morphogenesis is evagination of the optic vesicles, which occurs in the ventral forebrain during the final stages of neural tube formation (Fig. 3.1A). Detailed analyses have revealed changes in cell behavior that take place during the evagination process. In mouse, the cellular shape of optic vesicle cells changes dramatically, accompanied by transient alterations in basal lamina composition (Svoboda and OShea, 1987). In fish and frogs, ocular cells undergo

Patterning of the Optic Vesicle into RPE and Neural Retina

During evagination of the optic vesicle, the neural retina and RPE domains are specified (Fig. 3.2). The neural retina develops from the distal/ventral portion of the optic vesicle, while the RPE emerges from the dorsal region (Hirashima et al., 2008, Kagiyama et al., 2005). At the optic vesicle stage, the neuroepithelium is bipotential; the presumptive retina is competent to develop into RPE (Araki & Okada, 1977, Clayton et al., 1977, Horsford et al., 2005, Itoh et al., 1975, Opas et al., 2001

Optic Cup and Lens Morphogenesis

The distal portion of the optic vesicle makes contact with the overlying surface ectoderm, resulting in the specification of the lens ectoderm (preplacodal stage). This interaction leads to invagination of the lens placode and distal optic vesicle resulting in formation of a bilayered optic cup (Figs. 3.1B and 3.3). The neural retina and RPE develop from the inner and outer layer of the optic cup, respectively. The lens vesicle eventually separates from the surface ectoderm and differentiates

RPE Maintenance in the Optic Cup

Subsequent to initial establishment of the RPE in the optic vesicle, proliferation in the presumptive RPE ceases, leading to the formation of a single layer of cuboidal cells that become pigmented. As development proceeds, a period of differentiation and further maturation follows that results in dramatic morphological, structural, and functional changes of the RPE tissue such as formation of tight junctions, expansion of apical microvilli and invagination of the basal membrane, establishment

Concluding Remarks

In summary, several intrinsic and extracellular factors control different aspect of eye organogenesis. Though a lot of progress has been made demonstrating how these signals are connected in a network, in many cases, we do not know whether this regulation is direct, or how these interactions work at the molecular level. We also have still little insight into the actual output of these interactions. Finally, some processes during early eye development are still a mystery. For example, it is not

Acknowledgments

Special thanks to Julie Kiefer for critical reading and helpful suggestions on the chapter. My apologies to those authors whose work is not cited due to space limitations. This work was supported by NIH/NEI (EY014954 to S. F., Core Grant EY014800) and by an unrestricted grant from Research to Prevent Blindness, Inc., Department of Ophthalmology, University of Utah.

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