Skirball Institute of Biomolecular Medicine and Department of Cell Biology, NYU School of Medicine, 540 First Avenue, New York, NY 10016, USA
e-mail: treisman{at}saturn.med.nyu.edu
SUMMARY
The eye is an organ of such remarkable complexity and apparently flawless design that it presents a challenge to both evolutionary biologists trying to explain its phylogenetic origins, and developmental biologists hoping to understand its formation during ontogeny. Since the discovery that the transcription factor Pax6 plays a crucial role in specifying the eye throughout the animal kingdom, both groups of biologists have been converging on the conserved mechanisms behind eye formation. Their latest meeting was at the Instituto Juan March in Madrid, at a workshop organized by Walter Gehring (Biozentrum, Basel, Switzerland) and Emili Saló (Universitat de Barcelona, Spain), entitled `The genetic control of eye development and its evolutionary implications'. The exchange of ideas provided some new insights into the construction and history of the eye.
Origin of the eye
Darwin recognized that `organs of extreme perfection', such as the eye,
presented difficulties for his theory of evolution by natural selection. The
problem becomes even more daunting when one considers that the differences in
eye structure between different branches of the evolutionary tree imply that
complex eyes must have evolved independently at least 40 times
(Salvini-Plawen and Mayr,
1977). However, despite their morphological diversity, the eyes of
different organisms share many similarities, not only in function but also at
the molecular level. The most striking one is the presence in almost all eye
structures of the transcription factor Pax6
(Gehring and Ikeo, 1999
). In
Drosophila, as well as in vertebrates, Pax6 is both essential for eye
differentiation, and sufficient to induce eye development in certain regions
of the body (Chow et al.,
1999
; Halder et al.,
1995
; Hill et al.,
1991
; Quiring et al.,
1994
). This functional conservation of a specific transcription
factor implies a common evolutionary origin for all eyes. How can these
observations be reconciled?
A key to resolving this dispute is the definition of an eye. Walter Gehring
(Biozentrum, Basel, Switzerland), who first described the central role of Pax6
in eye formation (Halder et al.,
1995; Quiring et al.,
1994
), defines the prototypical eye, which was presumably the
common ancestor of all eyes, as the combination of a photoreceptor cell and a
pigment cell. This structure achieves some directional selectivity by using
screening pigment to block light coming from certain directions. Based on his
studies of diverse animal eyes, Michael Land (University of Sussex, Brighton,
UK) prefers to define an eye as an organ that can produce an image by
comparing the light intensities coming from different directions. To
accomplish this, it must contain photoreceptors with more than one spatial
orientation. Structures meeting this requirement range from simple pinhole
eyes, like that of Nautilus, to the compound eyes of insects and
molluscs and the complex camera eyes of cephalopods and humans, and may use
either lenses or mirrors to focus light onto the photoreceptors
(Land and Nilsson, 2002
)
(Fig. 1).
|
The arguments for the independent evolution of complex eye structures are
compelling, and include the use of spherical lenses in both vertebrates and
cephalopods despite the inverted organization of their retinas, and the
presence of compound eyes of differing organization in annelids, bivalve
molluscs and arthropods, as described by Land and Nilsson
(Land and Nilsson, 2002).
However, if we accept that the prototypical eye structure is the
photoreceptor/pigment cell combination, the conservation of Pax6 and rhodopsin
is suggestive of a monophyletic origin
(Gehring and Ikeo, 1999
). The
ciliary/rhabdomeric photoreceptor split could have either preceded or followed
the photoreceptor/pigment cell stage; in many species, ciliary photoreceptors
are not associated with pigment cells and may have a circadian rather than a
visual function (Arendt, 2003
;
Arendt and Wittbrodt, 2001
).
Additional genes could have been intercalated into the eye development
pathway, initially by simply providing them with transcriptional regulatory
elements that could be controlled by Pax6. Different intercalations in each
lineage would have allowed the evolution of diverse eye structures with a
variety of refractive or reflective surfaces.
An even more primitive structure is the eye organelle or eyespot, an
assembly within a single cell that contains both rhodopsin and screening
pigment, and sometimes even lens material. These subcellular organelles
probably first evolved in cyanobacteria
(Gartner and Losi, 2003), and
have been maintained either within or associated with chloroplasts (the
endosymbiotic descendants of these bacteria), in green algae such as
Chlamydomonas and Volvox
(Ebnet et al., 1999
;
Dieckmann, 2003
;
Dyall et al., 2004
). Eye
organelles containing rhodopsin are also present in dinoflagellates
(Greuet, 1965
;
Francis, 1967
;
Okamoto and Hastings, 2003
;
Ruiz-Gonzalez and Marin,
2004
), single-celled eukaryotes that have now lost the
chloroplasts in which these eyespots presumably originated. Gehring made the
intriguing suggestion that dinoflagellates might themselves have been engulfed
by larger creatures, such as Cnidarians, and may thus be the source of the
opsins and eye pigments of higher organisms.
If this scenario holds, at what point was Pax6 added to the mix? The
answer, as discussed by Zbynek Kozmik (Institute of Molecular Genetics,
Prague, Czech Republic), may lie in the jellyfish Tripedalia. This
organism has a PaxB gene that appears to be a hybrid between
Pax6 and Pax2/5/8, and that can both rescue a Pax2
mutant and induce ectopic eyes when transferred into Drosophila
(Kozmik et al., 2003). The
Tripedalia eye doubles as a balance organ, suggesting that
duplication of the PaxB gene in Bilateria may have resulted in
Pax6 becoming specialized to regulate eye development, while
Pax2/5/8 took control of the ear. Interestingly, although eyes
absent (eya) is downstream of Pax6 in the eye
development pathway in Drosophila
(Bonini et al., 1993
;
Halder et al., 1998
), mouse
Eya1 is not required in the eye but is crucial for ear development,
where it probably acts downstream of Pax2
(Xu et al., 1999
). The link
between eye and ear development was further confirmed by Francis Munier
(Hôpital Opthalmique Jules Gonin, Lausanne, Switzerland), who described
a new recessive human syndrome in which microphthalmia (small eyes) and other
eye abnormalities are combined with consistent defects of external ear
morphology.
Is Pax6 the master regulator?
There are some challenges to the primacy of Pax6 in eye development. For
instance, planarians are able to regenerate their eyes even when Pax6
is knocked down by RNA interference
(Pineda et al., 2002).
However, Emili Saló (Universitat de Barcelona, Spain) reported that
Pax6 is expressed in both the photoreceptors and the pigment cells of
planarians, and is likely to be functional there, as a GFP reporter driven by
three binding sites for the Pax6 homeodomain is specifically activated in the
eye in these animals, as well as many others
(Berghammer et al., 1999
;
Gonzalez-Estevez et al., 2003
;
Sheng et al., 1997
).
Regeneration may involve mechanisms distinct from those used in normal
development; Panagiotis Tsonis (University of Dayton, OH, USA) showed that the
secreted protein Sonic hedgehog plays a crucial role in lens regeneration in
the newt, although it is never expressed in the lens during development
(Tsonis et al., 2004
).
Another difficulty is the relatively late phenotype of mouse Pax6
mutants, in which the optic vesicle evaginates normally but fails to
differentiate further (Grindley et al.,
1995). Milan Jamrich (Baylor College of Medicine, Houston, TX,
USA) described another transcription factor, Rx (Rax Mouse Genome
Informatics), with an earlier role than Pax6. Rx is expressed in the
very early eye field, where its expression is independent of Pax6
(Zhang et al., 2000
). In its
absence, the optic vesicle fails to form
(Mathers et al., 1997
) and
Pax6 is not upregulated in the optic primordium
(Zhang et al., 2000
). However,
Rx acts only in the retinal part of the eye and not in the lens, and its
misexpression enlarges the retina but does not produce complete ectopic eyes
(Mathers et al., 1997
). In
addition, it is not required in eyes that use the rhabdomeric type of
photoreceptors. In Drosophila, Uwe Walldorf (Universität des
Saarlandes, Homburg/Saar, Germany) reported that Rx is required for
the development of the clypeus, a structure that pumps food into the digestive
system, and of central brain regions, but that its absence has no effect on
the eye (Davis et al., 2003
).
Using medaka and zebrafish models (Loosli
et al., 2003
; Loosli et al.,
2001
), Joachim Wittbrodt (EMBL, Heidelberg, Germany) has traced
the role of Rx in optic vesicle evagination to its ability to block the
epithelialization of neural tube cells. This produces a destabilized region of
the neural tube that can be pushed outwards by the forces of convergent
extension. It seems likely that the original function of Rx was to specify a
region of the anterior neural ectoderm from which eyes later developed in some
lineages (Fig. 2). Wittbrodt
suggests that ciliary photoreceptors originated in Rx-expressing
regions of the brain, and that Rx-induced morphogenetic movements brought them
into the periphery in vertebrates.
|
Constructing the eye from its building blocks
In order to produce an eye, the specification genes discussed above must
assemble all the necessary components. At the most basic level, the correct
number of cells must be generated in the appropriate region of the body.
Matthew Freeman (MRC Laboratory of Molecular Biology, Cambridge, UK) described
the control of cell proliferation during the second mitotic wave in the
Drosophila eye disc. Both phases of the cell cycle require specific
signals: Notch promotes the G1-S transition by increasing the transcription of
E2F-responsive genes and the expression of cyclin A, and the
Epidermal growth factor receptor (EGFR) pathway promotes mitosis by inducing
the transcription of string
(Baonza et al., 2002).
Activation of both pathways by signals from the developing ommatidia allows
the number of cells to be adjusted to match the requirement.
In the Drosophila eye, photoreceptors, cone cells and pigment
cells are all induced by the EGFR pathway
(Freeman, 1996), but in
vertebrates, the corresponding cell types arise from different tissues that
are separately regulated. Several talks addressed the question of lens
differentiation. Richard Lang (Children's Hospital Research Foundation,
Cincinnati, OH, USA) presented evidence that Wnt signaling may negatively
regulate lens formation. A conditional knockout of ß-catenin in regions
expressing a surface ectoderm/lens enhancer from the Pax6 gene
(Ashery-Padan et al., 2000
;
Williams et al., 1998
) leads
to the appearance of ectopic lentoid bodies anterior to the eye, whereas
expressing activated ß-catenin with the same enhancer blocks lens
invagination. These results invite comparison to the ectopic photoreceptor
differentiation induced by loss of Wingless (Wg) signaling in the anterior eye
disc of Drosophila (Ma and Moses,
1995
; Treisman and Rubin,
1995
). Markus Friedrich (Wayne State University, Detroit, MI, USA)
showed that Wg expression in this domain is also conserved in the grasshopper
(Friedrich and Benzer, 2000
).
Although it seems unlikely that this was a feature of the ancestral
Urbilaterian eye, it is possible that eyes have frequently formed just
posterior to a Wnt-expressing region that has come to set their anterior
limit.
Within the lens, crystallin expression must be activated to very high
levels. Ales Cvekl (Albert Einstein College of Medicine, Bronx, NY, USA) has
found that each crystallin gene is activated by a different combination of
transcription factors, including Maf, Sox, Six and Retinoic acid receptor
proteins, as well as two splice variants of Pax6
(Chauhan et al., 2004). These
regulatory pathways may be rapidly evolving. Joram Piatigorsky (National
Institutes of Health, Bethesda, MD, USA) has shown that the
B-crystallin promoter of the blind mole rat drives expression in
muscle, rather than lens (Hough et al.,
2002
). A potential Pax3-binding site in the promoter may be
responsible for this, as the introduction of a comparable site into the mouse
B-crystallin promoter decreases its activity in the lens and enhances
it in muscle. The disparate nature of crystallin proteins themselves raises
questions about their evolutionary origins. Many crystallins are heat-shock
proteins or enzymes, which may have acquired their refractive function simply
by becoming expressed at high levels in lens fiber cells. Zbynek Kozmik
(Institute of Molecular Genetics, Prague, Czech Republic) raised the
possibility that jellyfish may have acquired their crystallin genes by
horizontal gene transfer, as they are highly homologous to fish genes but are
not present in other animals. Piatigorsky reported that enzymes or other
ubiquitous proteins are also abundantly expressed in corneal cells in a
species-specific manner, suggesting that they have a structural or optical
function there (Piatigorsky,
2001
). An interesting example is gelsolin, an actin
filament-severing protein, which constitutes 50% of the water-soluble protein
in the zebrafish corneal epithelium (Xu et
al., 2000
).
The problem of photoreceptor differentiation was represented at the meeting
by Claude Desplan (New York University, NY, USA). Research in his laboratory
concerns the mechanisms by which Drosophila acquire color vision
(Cook and Desplan, 2001). For
example, the inner photoreceptors R7 and R8 express different rhodopsins
because of the presence of the transcription factors Prospero in R7
(Cook et al., 2003
) and
Senseless in R8. The exception to this rule is the dorsal rim area of the fly
eye, which is specialized to receive polarized light. The multifunctional
transcription factor Hth acts in this region to produce R7 and R8 cells that
express the same rhodopsin, and that extend their rhabdomeres one below the
other at right angles to form a polarizing filter
(Wernet et al., 2003
). In the
remainder of the eye, R7 cells are separated into two subsets that express
different rhodopsins by the apparently random activation of the bHLH-PAS
transcription factor Spineless.
Finally, Paola Bovolenta (Instituto Cajal, Madrid, Spain) focused on the
specification of the retinal pigment epithelium (RPE). She showed that the
transcription factors Otx1 and Otx2 both contribute to differentiating the RPE
from the neural retina (Martinez-Morales
et al., 2001). Otx proteins can act synergistically with
Microphthalmia-associated transcription factor (Mitf) to activate
melanosome-specific genes such as tyrosinase
(Martinez-Morales et al.,
2003
). As rhodopsin genes are also regulated by Otx proteins
(Chen et al., 1997
;
Tahayato et al., 2003
), the
use of Otx in the eye may date from the first cells that expressed both opsin
and pigment genes to produce an eye organelle. The complex developmental
mechanisms that have appeared since that time should inspire respect for what
evolution can achieve by, as Gehring put it, simply tinkering with existing
components.
ACKNOWLEDGMENTS
I thank Claude Desplan and Richard Lang for helpful comments on the manuscript.
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