Functional integration of eye tissues and refractive eye development: Mechanisms and pathways

Abstract

Refractive eye development is a tightly coordinated developmental process. The general layout of the eye and its various components are established during embryonic development, which involves a complex cross-tissue signaling. The eye then undergoes a refinement process during the postnatal emmetropization process, which relies heavily on the integration of environmental and genetic factors and is controlled by an elaborate genetic network. This genetic network encodes a multilayered signaling cascade, which converts visual stimuli into molecular signals that guide the postnatal growth of the eye. The signaling cascade underlying refractive eye development spans across all ocular tissues and comprises multiple signaling pathways. Notably, tissue-tissue interaction plays a key role in both embryonic eye development and postnatal eye emmetropization. Recent advances in eye biometry, physiological optics and systems genetics of refractive error have significantly advanced our understanding of the biological processes involved in refractive eye development and provided a framework for the development of new treatment options for myopia. In this review, we summarize the recent data on the mechanisms and signaling pathways underlying refractive eye development and discuss new evidence suggesting a wide-spread signal integration across different tissues and ocular components involved in visually guided eye growth.

Keywords: Chromatic aberrations; Crystalline lens; Emmetropization; Monochromatic aberrations; Myopia; Optical aberrations; Optical defocus; Refractive eye development; Signaling pathways.

Fig. 1.

Schematic diagram of vertebrate eye development and signaling pathways. The presumptive lens epithelium (A) starts to invaginate and forms the lens pits (B). The closure of the lens pits leads to the formation of the lens vesicles (B), which give rise to the lenses (C). Outpouchings of the neural tube give rise to the optic vesicles (A), which develop into the retinal pigment epithelium and neural retina (B and C). During eye development, BMPs produced by the surface ectoderm and presumptive lens epithelium play an important role in the development of the neural retina. TGFβ secreted by the periocular mesenchyme activates WNT/β-catenin signaling cascade and represses expression of Pax6 in the non-lens surface ectoderm, resulting in the suppression of the lens-fate pathways in the surface ectoderm outside the lens placode (A). In the lens placode, WNT/β-catenin signaling is inhibited by Pax6 that initiates lens development (A). The surface ectoderm secretes WNTs, which activate WNT/β-catenin signaling in the retinal pigment epithelium. This induces expression of Otx2 and Mitf, which control the developments of the retinal pigment epithelium (B). The FGF produced by the retina and vitreous promotes lens fiber differentiation (C). LP, lens pit; LS, lens; LV, lens vesicle; NR, neural retina; OV, optic vesicle; PLE, presumptive lens epithelium; POM, periocular mesenchyme; RPE, retinal pigment epithelium; SE, surface ectoderm; VT, vitreous.

Fig. 2.

Optical aberrations and refractive eye development. (A) Monochromatic aberrations, contributions of cornea and lens geometry, and retinal image quality. The wave aberrations of the eye influence retinal image quality and are produced, to a large extent, by imperfections in the cornea and the crystalline lens. The shapes of the cornea and the lens differ in emmetropes, myopes and hyperopes, suggesting that the optical aberrations may be linked to myopia development: (i) Corneal asphericity was found to be significantly more negative in myopes than hyperopes, resulting in significant differences in corneal spherical aberration; (ii) The crystalline lens geometry was found to change significantly with increasing myopia, i.e., the lens flattened and decreased in thickness. The inset shows examples of emmetropic and myopic lenses; (iii) Wave aberrations describe the optical quality of the eye. The modulation transfer function of the eye represents the contrast degradation as a function of spatial frequency. The Strehl ratio (area under the MTF normalized by diffraction) is often used as a retinal image quality metric; (iv) Age-related changes in retinal image quality (Strehl ratio) in a chicken model of myopia measured using Hartman-Shack aberrometry. Myopic eyes were found to be increasingly more aberrated than emmetropic eyes after day 6. (B) Longitudinal chromatic aberrations (LCA) arise from the wavelength-dependent differences in the refractive indices of the intraocular media: (i) In an emmetropic eye focused in green, red wavelengths will be focused behind the retina and blue wavelengths will be focus in front of the retina. Chromatic aberrations were suggested to play a role in accommodation and emmetropization; (ii) Monochromatic aberrations reduce the differences in image quality between L/M cones and S cones. cpd, cycles per degree; L, L cones; M, M cones; MTF, modulation transfer function; RAL, lens’s anterior radius of curvature; RPL, lens’s posterior radius of curvature; S, S cones.

Fig. 3.

Schematic diagram illustrating signaling cascade regulating eye emmetropization. The diagram shows the main processes, ocular tissues and the key tissue-specific signaling pathways found to be involved in refractive eye development. Postnatal eye growth is regulated by visual input. Visual form deprivation and hyperopic optical defocus stimulate eye growth, whereas myopic defocus inhibits it. The retina processes information about optical defocus and converts this information into molecular signals, which are transmitted across the retina, RPE and choroid to the sclera via a multilayered signaling cascade. In the retina, the signals generated by hyperopic and myopic defocus propagate via two largely distinct signaling cascades. These signaling cascades are organized into a highly integrated signaling network – the core component of the Bidirectional Emmetropization by the Sign of Optical Defocus (BESOD) mechanism which integrates visual stimuli and eye growth. The signals generated by optical defocus cause remodeling of the sclera and adjust the growth rate of the posterior segment of the eye to match the optical power of the eye with its axial length.