Eye morphogenesis and patterning of the optic vesicle

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.

Fig.3.1. Summary of early eye development in vertebrates

A) Factors from surrounding tissues (extraocular mesenchyme, optic stalk and surface ectoderm) regulate patterning of the neural retina and RPE in the vertebrate optic vesicle, which then expresses the specific transcription factors Vsx2 and Mitf, respectively. B) Invagination of the distal optic vesicle (presumptive retina) and the overlying lens placode results in formation of the optic cup and lens vesicle. For details, see text. Modified from Fuhrmann, 2008.

Fig.3.2. Specification of RPE and retina in the optic vesicle

The eye field transcription factors Pax6, Rx, Otx2, Six3 as well as Lhx2 are required in the optic vesicle to respond to inducing signals. A) RPE specification in mouse (early optic vesicle): the extraocular mesenchyme, possibly by producing an activin-like factor, induces Mitf expression in the entire optic vesicle. B) Retina specification in mouse and chick (late optic vesicle): subsequentially, activation of ERK, potentially through FGF secreted from the lens ectoderm, induces/maintains Vsx2 and Sox2 expression in the distal optic vesicle to promote retina development, which requires Vsx2-mediated suppression of Mitf.

Fig.3.3. Optic cup morphogenesis

Invagination of the lens placode requires correct specification of the lens ectoderm that is dependent on Six3-mediated maintenance and activation of Pax6 and Sox2, respectively. FGF and BMP signaling may be also required for lens induction. In the distal optic vesicle, BMP4 and BMP7 expression is crucial for specification of the lens ectoderm and for optic vesicle invagination. BMP expression requires activation by Lhx2 and FGF signaling. Not all of the mechanisms involved in the invagination process are shown here. For further explanation, see text.

Fig.3.4. Maintenance of the RPE in the optic cup

Several signaling pathways can regulate maintenance of cell fate in the presumptive RPE. For explanation, see text.