XB-ART-2702Int J Dev Biol January 1, 2004; 48 (8-9): 761-70.
Regulation of vertebrate eye development by Rx genes.
The paired-like homeobox-containing gene Rx has a critical role in the eye development of several vertebrate species including Xenopus, mouse, chicken, medaka, zebrafish and human. Rx is initially expressed in the anterior neural region of developing embryos, and later in the retina and ventral hypothalamus. Abnormal regulation or function of Rx results in severe abnormalities of eye formation. Overexpression of Rx in Xenopus and zebrafish embryos leads to overproliferation of retinal cells. A targeted elimination of Rx in mice results in a lack of eye formation. Mutations in Rx genes are the cause of the mouse mutation eyeless (ey1), the medaka temperature sensitive mutation eyeless (el) and the zebrafish mutation chokh. In humans, mutations in Rx lead to anophthalmia. All of these studies indicate that Rx genes are key factors in vertebrate eye formation. Because these results cannot be easily reconciled with the most popular dogmas of the field, we offer our interpretation of eye development and evolution.
PubMed ID: 15558469
Article link: Int J Dev Biol
Species referenced: Xenopus
Genes referenced: bmp4 cdknx cer1 chrd.1 foxg1 frs2 fst hes1 lhx2 mab21l2 neurog2 nodal nodal1 nog otx2 pax6 rax rpe six3 six6 tbx2 wnt1 zic2
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|Fig. 1. A schematic diagram of the regulatory interactions taking place during the specification of the retinal field. This simplified view shows that in the presence of BMP4 expression, the uncommitted ectoderm will form epidermis. As BMP4 is antagonized by chordin, follistatin or noggin, neural tissue will form. Additional inhibition of Wnt and/or nodal pathway is necessary to form anterior neuroectoderm. Anterior neuroectoderm expresses Otx2 that in turn, activates transcription of Rx. Rx performs several functions that are required for the formation of retinal progenitor cells. Rx promotes proliferation and inhibits differentiation of Rx expressing cells. At the same time, it increases transcription of several eye-specific genes like Pax6, Six3 and Lhx2. It also downregulates the transcription of Otx2 in the cells of the presumptive neuroretina. Since many of these regulatory interactions were not yet investigated in detail, it is important to emphasize that arrows between genes do not always imply direct regulatory interactions.|
|Fig. 2. Rx expression, phenotypes and regulation. (A-C) Expression pattern of Xrx1 in Xenopus embryos. (A) Anterior view of an early neurula stage embryo showing expression of Xrx1 in a single field. (B) Anterior view of a tadpole showing Xrx1 expression in the pineal gland (PG), ventral hypothalamus (VH), and two developing retinas (R). The cement gland (CG) does not express Xrx1. (C) A lateral view of a tadpole showing Xrx1 expression in the retina (R) and pineal gland (PG). Notice the lack of expression in the lens. (D) Effects of elimination of Rx function in mouse embryos. Comparison of the Rx-/- mouse embryo (right) with Rx+/- sibling demonstrates that Rx function is required for eye formation. (E,F) Elimination of Xrx1 function by Rx specific morpholino (RxMO) in Xenopus embryos results in the absence of eye formation. (E) Uninjected side of embryo showing normal eye development, while the eye is completely missing on the opposite, RxMO injected side (F). (G,H) Mutations in the human RX (RAX) gene cause anophthalmia. (G) Absence of ocular tissue in a patient with a mutation in RX gene. (H) CT scan of the same patient showing anophthalmic orbit (red arrow) and other orbit (red arrowhead). (I,J) Overexpression of Xrx1 RNA in Xenopus embryos results in overproliferation of the cells of the retina and anterior neural tube. (I) A cross section through a Xenopus embryo injected on the right side with Xrx1 RNA showing a duplication of the anterior neural tube and overproliferation of retinal cells. (J) Both the retinal pigment epithelium (RPE) and the neuroretina (NR) show overproliferation in this eye from an embryo injected with Xrx1 RNA. As a result, the RPE and the neuroretina show additional folding of the cell layers. (K,L). Regulatory elements of the Xrx1 direct GFP expression into the developing retina of Xenopus embryos. (K) Lateral view of a Xenopus embryo under transmitted light. (L) The same embryo viewed under fluorescence optics shows GFP expression in the developing retina. Images (A-C) and (I,J) are modified from Mathers et al., (1997), and images (K,L) are from Zhang et al., (2003). (D-H) are our unpublished data. CG, cement gland; NR, neuroretina; NT, neural tube; PG, pineal gland; R, retina; RPE, retinal pigment epithelium; SNT, secondary neural tube; VH, ventral hypothalamus.|