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 Evolution of vision and its relationship to ocular development (Evo‐Devo) More than any other organ, the eye has shaped the evolution of animals and ecosystems dating back to the Cambrian explosion. In animals, eyes use pin‐holes, lenses, mirrors and scanning devices in various combinations (see Land and Nilsson, 2002). Not all eyes are paired and placed on the head. Even a complex nervous system is not essential for their development as the box jellyfish has camera type eyes connected to a simple ring‐shaped nervous system. Eyes can be found in unicellular algaes (some dinoflagellatas) with a lens and a retina‐like structure all within one cell (see Gehring, 2004). The function of the eye adheres to specific laws of physics unique to vision. The human camera‐type eye contains three optically transparent tissues, the cornea, lens and retina. Light refraction depends on gradual changes in the refractive index of the ocular lens. The amount of light that can reach the retina is regulated by the contraction/expansion of the iris. Belonging to a family of sensory neurons, retinal photoreceptors convert light energy into electrical signals transmitted by the optic nerve to the brain. Ocular optics depends on the precise distance between the lens and retina that is partially regulated by intraocular eye pressure. Specialized trabecular meshwork cells in the anterior segment of the eye generate intraocular pressure. The evolution of the vertebrate eye has long served as one of the most intriguing problems of modern evolutionary and developmental biology. When Darwin thought of his theory of evolution, he recognized potential difficulties in its application to the problem of eye evolution. In “The Origin of Species”, Darwin summarized his concerns in the chapter “Difficulties of the Theory” in which he discusses “Organs of Extreme Perfection and Complication”. Modern biology has made enormous progress in its effort to explain the process of eye evolution. Data from genetic, biochemical and embryological studies have provided the current generation of researchers an indelible amount of information to analyze. Here, we will bring our focus to recent genetics studies that are beginning to greatly enrich our understanding of the evolution of the eye. The subject of eye evolution gained significant momentum due to the pioneering studies of W. Gehring and his co‐workers at the University of Basel (see Gehring and Ikeo, 1999; Gehring, 2004, 2005) A number of additional excellent review articles have recently covered this topic (Arnheiter, 1998; Bailey et al. 2004; Fernald, 2000, 2004; Kozmik, 2005; Land and Nilsson, 2002; Nilsson, 2004; Piatigorsky and Kozmik, 2004; Tomarev and Piatigorsky, 1997; True and Caroll, 2002; Wistow 1993, 1995). Similarly, a number of monographs have examined genetic networks relevant to eye development (see Davidson, 2000; Wilkins 2001; Schlosser and Wagner 2004). Studies of the simplest visual organs are consistent with the Darwinian prototype eye. Very primitive vision systems, such as those of the larval trematode worm, consist only of a single photoreceptor cell and a surrounding pigment cell (see Gehring and Ikedo, 1999). The worm senses light as a result of the coordinated actions of both cells: the pigmented cell screens the photocepter cell’s access to light by varying degrees to enable the latter’s ability to detect from where the light is coming (see Arnheiter, 1998; Nilsson and Land, 2002). Slightly more complex vision systems belong to certain forms of planarians that exhibit three photoreceptors alongside one pigmented cell (see Gehring, 2004). The existence of such distinct visual systems ranging from systems incapable of providing spatial vision to those capable of light detection, and finally to eyes with complex central nervous systems provides ample opportunity to investigate the reasons for their varying levels of complexity. An analysis of this information should enrich existing theories on evolution and broaden our understanding of ocular development in a number of model systems. Herein, we will focus on three aspects of eye evolution related to our ongoing work to understand lens development: 1. What are the essential proteins for vision and from where do they originate? 2. Evolution from the prototype ‘ancestor’ eye to the present‐day complex eye found in vertebrates. 3. What are the genes that regulate the formation of the eye and how do these genes function in different species? 1. What are the essential proteins for vision and from where do they originate? Herein, we summarize studies that show that molecules essential for visual systems in various animal lineages are both structurally and functionally related to proteins found in other tissues and organs. The key molecule for vision is rhodopsin because it is the molecule that detects light. Rhodopsin is a seven‐transmembrane (7‐TM) protein highly expressed in retinal photoreceptors. Microbial opsins (bacteriorhodopsins), with structural but not sequence homology with visual rhodopsins, are found in certain protists where they function as light‐
driven proton pumps (see Gehring, 2004; 2005). There is significant structural homology between bacteriorhodopsins and chemoattractant receptors regulated by cAMP. There are additional photosensitive molecules in unicellular algae including cryptochromes, phototropsins and photo‐activated adenylyl cyclases (see Nilsson, 2004). In addition to photoreceptors, other photosensitive cells, such as retinal ganglion cells that set the circadian clock, are present in the retina. In photosensitive iris cells and hypothalamic neurons, melanopsins detect light (see Arnheiter, 1998). Genes encoding rhodopsins and other genes encoding 7‐TM proteins can be analyzed for their evolutionary origin and distribution in individual species that do or do not possess eyes. Two signal transduction cascades operate downstream of rhodopsin. A rhabdomeric type of photoreceptor uses phospholipase C in the cascade. In this instance, light causes depolarization of the photoreceptor membrane potential. These photoreceptors are mostly found in invertebrate eyes. In contrast, ciliary photoreceptors, found in vertebrates, employ phosphodiesterase and signal transduction yields to the hyperpolarization of the photoreceptor membrane potential (see Nilsson, 2004). Cnidarians also have ciliary type photoreceptors. Since both these cascades are used for signal transduction in other cell types, it is evident that genes encoding proteins used to transduce light signals are evolutionarily related to other genes. An ocular tissue that increases our knowledge of eye evolution is the lens. Lens focuses the light on the retina. Although the lens is not found in the simplest form of the eye, it is a requirement for the camera type eye. Therefore, the evolutionary history of the lens reveals information regarding the types of improvements in vision necessary for color vision and function of the visual cortex. Camera type eyes are found in evolutionarily diverse vertebrates, cephalopods and cnidarians. Although these three types of lenses have different embryological origins (see Tomarev and Piatigorsky, 1996), they appear similar. This characteristic reflects their shared expression of water‐soluble proteins from the crystallin family. High levels of expression are required for lens transparency and its refractive index. Different members of this family mediate lens function in the aforementioned phyla. All vertebrate lenses contain α‐ and β‐crystallins. Two α‐crystallins, αA and αB, are structurally and functionally related to ubiquitously expressed small heat shock proteins. Six β‐crystallins are distantly related to microbial stress related proteins (see Wistow, 1995). They also share similarities with seven γ‐crystallins and are sometimes referred to as βγ‐crystallins. Invertebrate lenses and some vertebrate lenses also contain a special class of enzyme crystallins. Enzyme crystallins are identical or derived from basic metabolic enzymes. Avian genomes contain a pair of δ‐crystallin genes. Chicken δ2‐crystallin but not δ1‐crystallin is a functional enzyme argininosuccinate lyase (ASL) (see Piatigorsky 2003; Wistow 1995). Examples of additional enzyme crystallins are ζ‐crystallin/NADP quinone reductase in guinea pig and η‐crystallin/aldehydedehydrogenase 1 in elephant shrew (see Wistow, 1995). Genomic studies of crystallin genes identified gene duplication and changes in their regulatory mechanisms affecting their expression inside and outside of the lens. Crystallins served as the first example of the evolutionary strategy, termed “gene recruitment”(see Piatigorsky 2003). Crystallin gene recruitment by modifying the transcriptional program of “preexisting” genes appears to be a major molecular driving force of lens evolution. Evolutionary studies of genes that control brain development and higher brain function further support the role of changes in transcriptional programs during evolution (see Pichaud and Desplan, 2002; Khaitovich et al. 2005). 2. Evolution from the prototype ‘ancestor’ eye to the present‐day complex eye found in vertebrates. The issue of the evolutionary origin of the visual system can be divided into at least three phases. In the first phase, we need to explain the formation of photosensitive cells(s). In the second phase, we need to address the formation of the most primitive visual system. Finally, the formation of the primitive eye, prompts us to explain how this system led to the development of eyes of varying complexity. Herein, we will follow the hypothesis of the monophylogenetic origin of visual systems as proposed by W. Gehring (see Gehring and Ikeo, 1999; Gehring, 2004; 2005) and present data that weakens polyphyletic models of eye evolution proposed earlier (see Nilsson and Land, 2002). A Darwinian prototype eye that consists of a single photoreceptor cell and a surrounding pigment cell (see above) is actually found in certain flatworms and allows directional vision (see Gehring, 2004; 2005). It has been proposed that pigment cells may in fact be evolutionary precursors to photoreceptor cells (see Arnheiter, 1998). An intriguing possibility exists that pigmented skin cells performed thermoregulation and photoprotection prior to their ability to detect light. An ancestral animal with melanopsin‐expressing pigment cells in its skin might have evolved into an organism with a rhodopsin‐expressing pigment cell by gene duplication and mutagenesis followed by evolutionary selection. To address Darwins’s problem with “Organs of extreme Perfection and Complication”, Gehring argues that “the evolution of an eye prototype would seem to be a highly improbable stochastic event, since selection can only work after the various components are assembled into a prototype that is at least partially functional as a photoreceptor organ” (see Gehring, 2004). Hence, the hypothesis of the polyphyletic origin of the eye, arising as much as 65 times independently in history (see Nilsson and Land, 2002), is incompatible with the basic concept of evolution by natural selection. In contrast, molecular studies (see next paragraphs) are compatible with the monophylogenic origin of the eye. Finally, an important issue concerns the reconciliation of the evolutionary model of the eye with fossil records. Studies of fossils suggest that the most active period in eye evolution occurred just prior to and continuing into the Cambrian explosion (543‐520 million years ago) (see Nilsson, 2004). Fossils from the pre‐Cambrian era show no obvious records of bilaterians, but cnidarians appear to have been abundant. Concerning the time needed for the evolution of a camera‐like eye, a theoretical model by Nilsson and Pelger yielded the estimate that less than 400,000 generations are needed for such a process. Hence, less than half a million of years is the time needed, a fraction of the pre‐Cambrian and Cambrian eras, to generate a complex eye from its prototype. 3. Which genes regulate eye formation and how do these genes function in different species? Identification of regulatory genes that control eye development contributes significantly to our thinking about the evolution of the eye. Gehring’s argument about the monophylogenic origin of the eye is supported by a series of findings that evolutionary conserved gene Pax6 controls eye development in a number of vertebrates and invertebrates. A Pax6‐related gene, PaxB, was found in cnidarians and was implicated in eye and statocyst development (see Kozmik, 2005). In mammalian embryos, Pax6 is expressed in every important ocular tissue. Pax6 is expressed in the surface ectoderm that gives rise to the lens and corneal epithelium. Pax6 is also expressed in the neuroectoderm that forms the neuroretina, retinal pigment epithelium and parts of the iris. Pax6 is transitionally expressed in neural crest cells that form the corneal endothelium, keratocytes, parts of the iris and trabecular meshwork. However, Pax6 is not expressed in vertebrate photoreceptors. In Drosophila compound eye, Pax6/eyeless, is expressed in the eye imaginal disk, an epithelial sheet of cells that differentiate into photoreceptors and other cells of the adult fly eye. Evidence was obtained that eyeless binds to orthologous regions of multiple Drosophila rhodopsin promoters during its reexpression phase in mature photoreceptors (Sheng et al. 1996). The foundation for Gehring’s evolutionary model is that Pax6 controls rhodopsin expression. Studies of cnidarian (jellyfish Tripedalia) PaxB indeed have shown binding to the Drosophila rhodopsin regulatory element (Kozmik et al. 2003). Evolution of the eye can be explained using the “intercalary” mechanism (see Gehring and Ikedo, 1999). Darwin’s prototype of the eye has two genes, Pax6 and its target, ancestral rhodopsin. An increasingly more complex eye can be generated by intercalation of novel genes into this relationship. For example, Pax6 directly regulates lens crystallins (see Cvekl and Piatigorsky, 1996). Pax6 binding sites are shown in vertebrate and invertebrate crystallin gene promoters as shown in Fig. 1. More importantly, taxon‐specific crystallins such as chicken δ1‐ and guinea pig ζ‐crystallin/NADP quinone reductase were shown to be directly regulated by Pax6 (see Cvekl and Piatigorsky, 1996). An insertion of a genomic fragment containing Pax6‐binding sites 5’‐of the ζ‐crystallin promoter (see Wistow, 1995) or into the 3rd‐intron of the ancestor δ‐crystallin gene is illustrated in Fig. 2. It is also possible to hypothesize that a regulatory region in one gene encoding ancestral small heat shock protein was convesrted into a pax6‐binding sites by just three nucleotide substitutions (see Fig. 3). The recruitments of enzyme crystallins are relatively recent evolutionary events to lens function in specific animal lineages and provide direct evidence for intercalary evolution. Furthermore, Pax6 regulates the expression of specialized regulatory genes required for eye formation in the mouse and fly. The most documented examples are homeobox containing genes, Six3/sine oculis (so), and structurally unclassified genes, Mab21, that are regulated by Pax6 in these two diverse systems (see Lang, 2004; Michaut et al. 2003). Thus, current data show that the key regulatory gene for eye development Pax6/eyeless regulates expression of many regulatory and structural proteins required for vision. New data from molecular studies of visual system development in both vertebrates and invertebrates combined with analysis of genomes from these species and species that do not have visual systems will generate additional data to further our understanding of the evolution of vision. References Arnheiter (1998) Nature 391:632‐633. Bailey et al. (2004) Int. J. Dev. Biol. 48:761‐770. Cvekl and Piatigorsky (1996) Bioessays 18:621‐630. Cvekl et al. (2004) Int. J. Dev. Biol. 48:829‐844. Czerny et al. (1999) Mol. Cell 3:297‐307. Davidson (2001). In Genomic regulatory systems. Academic Press, San Diego. Fernald (2000). Curr. Opin. Neurobiol. 10:444‐450. Fernald (2004) Int. J. Dev. Biol. 48:701‐705. Gehring and Ikeo (1999) Trends Genet. 15:371‐377. Gehring (2004) Int. J. Dev. Biol. 48:707‐717. Gehring (2005) J. Hered. 96:171‐184. Khaitovich et al. (2005) Science 309:1850‐1854. Kozmik et al. (2003) Dev. Cell 5:773‐785. Kozmik (2005) Curr. Opin. Genet. Dev. 15:1‐9. Land and Nilssson (2002) In Animal eyes. Oxford University Press, Oxford. Lang (2004) Int. J. Dev. Biol. 48:783‐792. Michaut et al. (2003) Proc. Natl. Acad. Sci. USA 100:4024‐4029. Nilsson (2004) Curr. Opin. Neurobiol. 14:407‐414. Piatigorsky (2003) J. Struct. Funct. Genomics 3:131‐137. Pichaud and Desplan (2002) Curr. Opin. Genet. Dev. 12:409‐415. Relaix and Buckingham (1999) Genes Dev. 13:3171‐3178. Schlosser and Wagner (2004). In Modularity in development and evolution. The University of Chicago Press, Chicago. Sheng et al. (1996) Genes Dev, 11:1122‐1131. Tomarev and Piatigorsky, (1996) Eur. J. Biochem. 235:449‐465. True and Caroll (2002) Annu. Rev. Cell Dev. Biol. 18:53‐80. Wilkins (2002) in The evolution of developmental pathways. Sinauer, Sunderland. Wistow (1993) Trends Biochem. Sci. 18:301‐306. Wistow (1995) in Molecular biology and evolution of crystalline genes: gene recruitment and multifunctional proteins in the eye lens. Springer‐Verlag, Heidelberg. Yao and Sun (2005) EMBO J. 24:2602‐2612. Zhang and Emmons (1995) Nature 377:55‐59. © 2006 Figure 1. A diagrammatic summary of promoters encoding vertebrate and invertebrate crystallins.
Maf responsive element, MARE; retinoic acid responsive elements, RARE; and cAMP responsive
elements, CRE are shown in orange, light yellow and yellow, respectively. Note that all these promoter
contain Pax- and large Maf-binding sites (see Cvekl et al. 2004).
Figure 2. Diagram of ζ-, δ- and τ-crystallin genes (adopted from Wistow, 1993;1995). ζ-crysallin
locus is transcribed from two promoters. The proximal, lens specific promoter contains MARE/Pax6binding sites. Avian δ-crystallin loci contain insertion of a lens-specific enhancer in the third intron.
This insertion is absent in mammalian genomes.
Duck τ-crystallin locus has TATA-box in the promoter like the majority of crystallin promoters. Pax6binding sites in this locus remain to be studied.
Figure 3. A model to explain conversion of ancestral small heat shock protein gene promoter into a
Pax6-responsive promoter. Note that a strong Pax6-binding site contains motifs recognized by heat
shock transcription factors and AP-1 proteins.