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???displayArticle.abstract??? Lens development is a stepwise process accompanied by the sequential activation of transcription factors. Transcription factor genes can be classified into three groups according to their functions: the first group comprises preplacodal genes, which are implicated in the formation of the preplacodal ectoderm that serves as a common primordium for cranial sensory tissues, including the lens. The second group comprises lens-specification genes, which establish the lens-field within the preplacodal ectoderm. The third group comprises lens-differentiation genes, which promote lens morphogenesis after the optic vesicle makes contact with the presumptive lensectoderm. Analyses of the regulatory interactions between these genes have provided an overview of lens development, highlighting crucial roles for positive cross-regulation in fate specification and for feed-forward regulation in the execution of terminal differentiation. This overview also sheds light upon the mechanisms of how preplacodal gene activities lead to the activation of genes involved in lens-specification.
Fig. 1. Schematic illustration of vertebrate lens development, relationships between inductive interactions and sequential activation of transcription factors. (A–G) Xenopus was chosen as the vertebrate representative since its developmental lineages of lens, retina and other related tissues have been well studied ( [Eagleson and Harris, 1990] and [Eagleson et al., 1995]). The developmental stages are indicated at the top of the figure. (A) Dorsal view of a neural plate-stage embryo (anterior at the top of the image) indicating the preplacodal ectoderm (PPE, purple), the presumptive lensectoderm (PLE, dotted light blue), the neural plate (NP, light orange), and the presumptive retina field (PR, dark orange). (B) Transverse section of a neural plate-stage embryo through the PLE and PR. The red line in A indicates the plane of the section. Lens and retina lineages are shown in light blue and dark orange, respectively, in B-G, and mesoderm and endoderm (ME) are shown in light green. (C) Transverse section of a neural tube-stage embryo where the optic vesicle (OV), which develops from the PR, reaches the PLE. (D-F) Close-ups showing lens vesicle formation. The PLE overlying the OV becomes thickened to form the lens placode (LP), which subsequently separates from the headectoderm to form the lens vesicle (LV). OC, optic cup. (G) Close-up of a maturating lens. LE, lensepithelium; LF, lens fiber; NR, neural retina. (H) Major signaling factors are indicated in red with dotted gray arrows. FGF signaling from the neural retina is responsible for the formation of the secondary lens fibers from the lensepithelium (Lovicu and McAvoy, 2005). The other signaling pathways are explained in the text. At the bottom, Expression profiles of preplacodal genes, lens-specification genes and lens-differentiation genes (pink, green, and blue arrows, respectively) studied in Xenopus, zebrafish, chicken and mouse embryos. The dotted blue lines of FoxE3 and Pitx3 represent species differences in initial expression profiles. Details and references are described in the text. (I) In situ hybridization analysis of Pax6 expression in a neural plate-stage Xenopus embryo (dorsal view). The PLE and PR are indicated. The boundary between the neural plate and PPE is indicated by a white broken line. Note that preplacodal Pax6 expression occurs broadly adjacent to the anterior margin of the neural plate.
Fig. 2. Genetic pathways for the induction of lens differentiation from the PPE. The pathways were deduced from gene interactions characterized in Xenopus, zebrafish, chicken and mouse, and depicted using BioTapestry (Longabaugh et al., 2005). Each gene is indicated by a short horizontal line that represents its cis-regulatory region and a bent arrow that represents its transcription start site. Solid lines connecting genes indicate direct gene interactions revealed by cis-regulatory analyses, and dashed lines connecting genes indicate gene interactions characterized by loss-of-function and/or gain-of-function experiments. Of the lines indicating gene interactions, those with an arrow at the end and those with a short horizontal line at the end indicate activation and repression of downstream genes, respectively. The bold lines highlight cross-regulatory interactions between Pax6, Sox2 and Six3, and feed-forward regulation involving Maf genes. Letters (X, Z, C, M) beside lines representing gene interactions indicate the model animals (Xenopus, zebrafish, chicken, and mouse) in which the interaction was identified, respectively. The funnel-like symbols and open circle indicate receptors and a downstream signal transducer, respectively. Tissues are identified using different background colors.
Fig. 3. Cis-regulation of mouse Pax6 and chicken δ-crystallin genes. For Pax6, only two enhancers active in the lens lineage, EE and SIMO, are shown, although this gene has other enhancers for other tissues, such as retina and diencephalon. The SIMO element is located approximately 82 kb downstream of the last exon of Pax6. Pax6 has two promoters, P0 and P1 (Xu et al., 1999b). In EE, the 5′-most Sox-binding site overlaps with both Pou2f1- and the 2nd Sox-binding sites, and the 2nd Sox-binding site overlaps with the 3′-most Sox-binding site. Meis1, Meis2 and Prep1 recognize the same binding sites. The lens enhancer of the δ-crystallin gene is located in the 3rd intron. This enhancer is activated in lens epithelial cells by Pax6-binding to the 3′ site, which depends on neighboring Sox2/Sox3-binding, as described in the main text. L-Maf-binding to the flanking sites strongly activate this enhancer in lens fiber cells ( [Ogino and Yasuda, 1998] and [Shimada et al., 2003]), whereas the 5′-most Pax6-binding attenuates the enhancer activity (Muta et al., 2002).
