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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 ventralhypothalamus. 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.
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15558469
???displayArticle.link???Int J Dev Biol ???displayArticle.grants???[+]
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), ventralhypothalamus (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, ventralhypothalamus.
