Eye Degeneration Cavefish

Studies have been performed with Astyanax mexicanus to investigate the progression of eye degeneration because this species has an eyed surface-dwelling form and several eyeless cave-dwelling forms that are able to interbreed [1]. The two forms of the same species allows Asytanax mexicanus to be great candidates for eye degeneration experiments because eye development can be studied by comparing the results for cavefish populations while using the surface-dwelling populations as a control. While, the reason for eye degeneration in cavefish has not been conclusively resolved, there are several theories that try to explain the evolution process [2].

In order to understand what occurs during eye degeneration, normal eye development must be appreciated. The lens vesicle, optic cup with inner and outer retinal layers, and optic stalk are the constituents of the eye primordia, which are formed in the first stage of eye development. First, the optic vesicles develop on the left and right sides of the brain. The optic vesicles then extend and expand toward the surface ectoderm and form optic stalks. At the distal edge of the optic stalks, the cells begin to fold inward forming the optic cups. Simultaneously, surface ectoderm near the optic vesicles begins to thicken and forms the lens vesicle. The lens vesicle then pinches off and protrudes into the optic cup [2]. Also, cell division and differentiation occur in this stage of eye development, especially in the retina, which will continue to grow in two main areas: the ciliary marginal zone and the inner nuclear layer. In the ciliary marginal zone, stem cells grow in the area where the retina meets the iris, producing neural and glial cells as well as retinal pigment epithelium. In the inner nuclear layer, stem cells produce rod precursors that will later become rod photoreceptors [4].

The eye will continue to undergo cell division and get larger marking the second stage of eye development. During this phase, cell division occurs in the marginal epithelial zone to generate secondary fiber cells, which along with primary fiber cells form the core of the lens [2]. The ciliary margin zone is a ring of undifferentiated cells that undergoes continuous cell division at the distal end of the optic cup. These new cells do not actually migrate, but slowly begin to shift into the retina for further development and specialization as new cells rings are produced [7]. The iris, ciliary body, and cornea are formed when new cells are created from the cranial neural crest and migrate to their corresponding optic regions. Lastly, the sclera is formed. Sclera is a thin cartilaginous or bony tissue that is formed from neural crest cells and will encase the interior portion of the eye [2].

In the development of the cavefish embryo, normal eye development occurs initially (Figure 1). However, development soon stops and begins to deteriorate. It appears that lens apoptosis, programmed cell death, is the signal for the eye degeneration of the Asytanax cavefish populations [1, 3]. Apoptotic lens cells are detected early in cavefish embryo development; around the time that the lens vesicle pinches off the surface ectoderm. Thus, it appears that for the cavefish, the lens cells are destined to die rather than multiply [2], which in turn sets up a chain of events for the rest of the deterioration of the eye. The retina, without the presence of a functional lens, begins to become disorganized, causing the appearance of apoptotic cells and the disappearance of photoreceptor cells. Even though the cavefish eye is deteriorating, new cell growth in the lens and retina is still occurring during this time, but they are constantly being removed [4]. Therefore, it is not that cell proliferation is inhibited, but rather that there is no cell differentiation and, thus, no substantial increase in eye mass. Apoptosis dominates in the cavefish lens causing the little retina that remains to sink into the eye orbit [2] and be covered over with skin [1].

To experimentally prove that lens apoptosis is a key factor in eye degeneration, lens transplantations from surface fish into cavefish and vice versa were performed. In these experiments the lens vesicle from the surface fish or cavefish embryo was transplanted into an optic cup of the cavefish or surface fish, respectively. The other eye on each Astyanax species was left undisturbed to act as a control. The results: eye development was stimulated in the cavefish and eye degeneration occurred in the surface fish [1]. Considerable improvement in the retinal growth, development of new optic nerve fibers, and photoreceptor differentiation occurred in the cavefish [4], while lens vesicle death, arrested growth, and eventually the disappearance of the eye into the orbit occurred in the surface fish. The control side degenerated or developed normally as expected (Figure 2). Surprisingly, bone structure around the eye was also induced from the transplantation, suggesting eye growth has an impact on craniofacial morphology [2]. This reversal of eye degeneration shows that, at the time of the transplantation, lens apoptosis has already been programmed. It also shows that normal eye development is dependent on the existence of a functional lens [2, 4].

Though the lens plays a critical role in eye degeneration, genetic factors need to be considered as well. One such genetic factor is pax6, a transcription factor that is known to have a role in eye development for both invertebrates and vertebrates. Pax6 is expressed in cavefish lens placodes and has been assayed to show that no mutations have occurred to possibly cause a loss of function. However, reduced pax6 expression has been detected in cavefish due to down regulation [3]. This reduction in expression leads to smaller size of optic vesicles and production of a midline gap, a gap that that does not occur in surface fish.

Pax6 is also known to correlate with pax2a; therefore, changes in pax2a expression were expected. This is exactly the case, but instead of having a reduced expression as was the case with pax6, pax2a expression was increased leading to enlargement of the optic stalk [2].

Hedgehog signaling also seems to play a role in eye degeneration because of the activation of hsp90α, a heat shock protein, as a target. While the mechanics of how hedgehog signaling affects lens apoptosis is unclear, TUNEL labeling shows that hsp90α expression peaks shortly before the beginning of lens apoptosis signifying a strong correlation [2, 5].

While more work is being done to understand the process of eye degeneration, there is little evidence for why this eye loss occurred in cavefish populations. Two opposing hypotheses are the neutral mutation hypothesis and the adaptation hypothesis. The neutral mutation hypothesis implies that by the natural random occurrence of mutation within the genome and the little selective pressure on cavefish for the upkeep of the eye in the dark environment, the eye is destined to degenerate by the accumulation of the now mutated eye forming genes. The adaptation hypothesis, on the other hand, implies that eye degeneration is actually adaptive because of its advantages in the dark environment due to the exchange of eye formation for the enhancement of other sensory organs [2]. While there are critics to both hypotheses, current thinking unites the two by assuming that eye degeneration occurred in two steps based on the evolutionary force of pleiotropy. Pleiotropy is the ability of a single gene to have more than one distinguishable effect, such as positively regulating one trait and negatively regulating another [2, 6]. The first step in this hypothesis is that natural selection may have selected for pleiotropic genes in the expanded midline in cavefish populations, causing enhancement of taste buds and other sensory organs over the formation of whole eyes because of their relative unnecessary function in the cave environment. Then as a result of the lax selection pressure for the eye, neutral mutations could accrue and cause further eye degeneration over time [3].

Another question arises when studying eye degeneration. Did all cavefish populations originated from one ancestor or did cavefish populations arise multiple times? According to R.W. Mitchell's research done in the 1970s, the divergence between surface fish and cavefish occurred several times in the Sierra de El Abra region around 10,000 to 100,000 years ago. Thus, some of the cavefish populations may have developed eye degeneration in parallel with each other [2, 3]. This likelihood is supported by the studies of DNA polymorphisms and mtDNA. The phylogenetic studies using DNA polymorphisms showed two origins of cavefish populations, one in Sierra de El Abra region and the other in the Micos region (Figure 3). However, this analysis is slightly questionable because of the difficulty in obtaining an adequately variable sequence between the populations. The mtDNA analysis also shows two origins: one before the Astyanax mexicanus and Astyanax aeneus split and the other occurring after the split. These two lineages are genetically isolated, but the analysis was performed on only one gene [3]. In any case, it is probable that separate origins of the cavefish populations have

occurred and eye degeneration evolved multiple times [1].

Astyanax mexicanus has been studied extensively to learn the evolution of eye degeneration through lens transplantation experiments and genetic marker studies. From these experiments researchers now know that lens apoptosis, pax6, and pax2a are key factors in eye loss for cavefish populations. Two opposing theories have been proposed to explain eye degeneration, but there seems to be no clear cut evidence for one over the other. However, a united theory combining elements from the neutral mutation hypothesis and adaptation hypothesis has been presented and best explains the process for the current knowledge available. Nonetheless, it is highly probable that eye degeneration has evolved multiple times and is beneficial for this species through the enhancement of other sensory organs.

Bibliography

Yamamoto, Y., Jeffery, William R. (2000) Central role for the lens in cave fish eye degeneration. Science 289: 631-633.

Jeffery, William R. (2005) Adaptive evolution of eye degeneration in the Mexican blind cavefish. Journal of Heredity 2005: 185-196.

Jeffery, William R., Strickler, Allen G., Yamamoto, Yoshiyuki. (2003) To see or not to see: evolution of eye degeneration in Mexican blind cavefish. BioOne 43: 531-541.

Strickler, Allen G., Yamamoto, Y., Jeffery, William R. (2007) The lens controls cell survival in the retina: evidence from the blind cavefish Astyanax. ScienceDirect 2007: 512-523.

Hooven, T., Yamamoto Y., Jeffery, W. (2004). Blind cavefish and heat shock protein chaperones: a novel role for hsp90α in lens apoptosis. The International Journal of Developmental Biology 48: 731-738.

"Pleiotropy." Biology Online. 03 OCT 2005. 12 Apr 2008 <http://www.biology-online.org/dictionary/Pleiotropy>.

Harris, William A., Perron, Muriel. (1998) Molecular recapitulation: the growth of vertebrate retina. The International Journal of Developmental Biology 42: 299-304.

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