Early divergence of central and peripheral neural retina precursors during vertebrate eye development

Abstract

Background: During development of the vertebrate eye, optic tissue is progressively compartmentalized into functionally distinct tissues. From the central to the peripheral optic cup, the original optic neuroepithelial tissue compartmentalizes, forming retina, ciliary body, and iris. The retina can be further sub-divided into peripheral and central compartments, where the central domain is specialized for higher visual acuity, having a higher ratio and density of cone photoreceptors in most species.

Results: Classically, models depict a segregation of the early optic cup into only two domains, neural and non-neural. Recent studies, however, uncovered discrete precursors for central and peripheral retina in the optic vesicle, indicating that the neural retina cannot be considered as a single unit with homogeneous specification and development. Instead, central and peripheral retina may be subject to distinct developmental pathways that underlie their specialization.

Conclusions: This review focuses on lineage relationships in the retina and revisits the historical context for segregation of central and peripheral retina precursors before overt eye morphogenesis.

Keywords: avian eye; fate map; lineage; optic cup; optic vesicle.

Figure 1. Optic Cup Tissues

Scheme of a sagittal section through the mature eye, depicting the central (posterior) to peripheral (anterior) arrangement of optic tissues. The ciliary body, iris, and lens are collectively called the anterior segment of the eye. L-lens, C-central, P-peripheral, D-dorsal, V-ventral, OCL-optic up lip, IE-iris epithelia, CE-ciliary epithelia, os-ora serrata, NR-neural retina, pNR-peripheral neural retina, cNR-central neural retina.

Figure 2. Models of Eye Development

(A) Single retinal origin model of eye development place a single neural precursor (red) at the distal OV. Anterior eye tissues, ciliary body and iris (green), arise from the boundary between NR and RPE (yellow) precursor zones. The entirety of the NR is derived from a single precursor domain at the distal OV. (B) Dual retinal origin model of eye development. The retina can be divided into two domains, central (red) and peripheral (green), based on their OV origin. The cNR precursor is positioned at the caudal OV. The peripheral NR shares an OV origin with anterior eye tissues. OV-optic vesicle, pc-prechordal plate, m-paraxial mesoderm, L-lens; CB-ciliary body, axis points: R-rostral, C-caudal, ce-central, p-peripheral, D-dorsal, V-ventral.

Figure 3. Lineage relationships during eye morphogenesis

(A–E) Schematic views of eye at optic vesicle (A), early (B), and definitive (C) optic cup stages in wholemount (A–C) and section (D and E) view. Cells along the rostrocaudal axis of the distal optic vesicle (A, pale blue, green purple dots) distribute along the nasotemporal OCL axis of the early optic cup (pale blue, green, purple sectors in B. Labeling the early OCL (darker blue, green, purple dots, B) results in radial distribution of marked cells from the peripheral towards the central optic cup (C and E). Non-OCL label is displaced to the posterior over time (orange dots, B, C). The ventral optic cup is labeled after tagging progenitors at the newly formed ventral OCL (brown dots, B, C, E); cells expand circumferentially in the ventral domain as development continues. In section view (D and E), OV label at the caudal OV (red, A) and dorsal OV (yellow, A) are restricted to the central neural retina and central retinal pigmented epithelium (red and yellow label, D and E). (E) Representative distribution from OCL labeling of a subpopulation of the dorsal (dark green) and ventral (brown) OCL following several days of development. Pc-prechordal plate, m-paraxial mesoderm, L-lens, os-optic stalk, e-surface ectoderm, OCL-optic cup lip, R-rostral, C-caudal, pr-proximal, d-distal, D-dorsal, V-ventral, N-nasal, T-temporal.

Figure 4. Peripheral eye domain retains multipotency through optic cup morphogenesis

Wholemount (A) and sectional (B–D) representation of HH Stage 4 embryo (A), optic vesicle (B), early (C) and later (D) optic cup stage eyes. (A) Eye forming potential was seen rostral to the primitive streak (grey). RPE and neural retina were formed from lateral tissue (pink) and RPE from medial tissue (blue). (B) The distal optic vesicle (magenta) is multipotent in respect to its normal contribution to inner and outer optic cup and, subsequently, multiple eye tissues. A caudal optic vesicle domain (blue) is restricted to a single, central neural retinal fate. (C, D) With development, multipotency is retained in the OCL in optic cup and fate-restricted tissue throughout the rest of the eye. ps-primitive streak, OV-optic vesicle, cNR-central neural retina, m-paraxial mesoderm, e-ectoderm, L-lens, cRPE-central retinal pigmented epithelium, OCL-optic cup lip, pNR-peripheral neural retina, pRPE-peripheral retinal pigmented epithelium, R-rostral, C-caudal, D-dorsal, V-ventral.

Figure 5. Summary of optic vesicle domains identified through direct lineage analysis and ablation experiments

(A) Schematic of optic vesicle to demonstrate major axes and (B) Rotated views and simplified graphics to highlight an individual axis. (C) Comparison of results of direct lineage analysis: (i) derived from non-diluting permanent retroviral tagging; (ii) from DiI membrane labeling. As in Figure 4, magenta indicates multipotent progenitor domains and blue indicates restricted domains, giving rise to only central neural retinal tissue. (D) Summary of several ablation studies, in which an optic cup was formed and analyzed for early morphology, see text for details. (E) Summary of ablation studies, in which an optic cup was formed and analyzed for mature features, either photoreceptor complement or retinotectal projection, see text for details. D-dorsal, V-ventral, N-nasal, T-temporal, R-rostral, C-caudal.

Figure 6. Optic cup morphogenesis

(A) Scheme of the head region of a neural fold stage (HH8) embryo highlighting areas that distributed to optic tissue (grey), central (red) and peripheral (green) neural retina in mature optic cup. (B–F) Sectional representation of progressive stage of eye development. Fate mapped regions are marked with colour, see key below. Broad proliferation zones are indicated by bars. (B) Optic vesicle before lens placode formation in two different views: coronal (top) and transverse (lower) view. Tagged domains not in section plane are indicated by arc. (C–F) Schematic sections present dorsal-ventral view of eye. (C) Transitional stage of OV to OC morphogenesis with a distinct lens placode. (D) Invaginating OV and developing lens vesicle. (E) Early OC with lens. The ventral OC has not formed. (F) OC and lens. Dorsal and ventral OC domains have formed. KEY: Yellow-dorsal OV, green-distal OV, red-caudal OV, blue-ventral, proximal OV. OV-optic vesicle, OC-optic cup, L-lens, e-ectoderm