Why Can’t Eye See Anymore?

by Amanda H Wen, Scripps College [edited by Lars Schmitz as part of BIOL 167 “Sensory Evolution”, an upper division class at the W.M. Keck Science Department. Written for educational purposes only].

Considering the importance of sight for most vertebrate organisms in both food foraging and predator evasion, it can be difficult to conceptualize the idea of an evolutionary shift towards blindness. This difficulty may be because vision is seen as one of the primary sensory mechanisms for engaging in an environment. Even many aquatic animals have specialized eyes, most likely due to the increased difficulty that comes with underwater vision. Consequently, one might expect that most highly developed eyes belong to organisms that live in habitats that are not conducive to vision. However, this hypothesis has not necessarily been supported by evidence. In fact, studies have shown that many animals native to environments that are difficult to navigate visually have instead lost the ability to see entirely, in exchange for alternate means of sight that are more energetically favorable.

One such curious case in the world of evolution is the loss of eyes in the Mexican blind cave fish, Astyanax mexicanus. These fish are native to underwater caves in northeastern Mexico, and are found in completely dark environments (Yoshizawa et al., 2012). The limited amount of light, in addition to the underwater environment, has pushed natural selection towards an alternate means of “sight.”

These effects have been compound so greatly over time that the physical eye structure has been almost entirely eradicated (Figure 1). Alternatively, the Mexican blind cave fish have been shown to possess genes that produce mechanisms that are sensitive to water pressure and object vibrations; the acquisition of these genes may be directly correlated to the loss of their eyes. (Yoshizawa et al., 2012). This is because evolution tends to favor the more efficient option, rather than put resources towards redundant or unnecessary functions; and having two mechanisms for navigation around their environment is very metabolically

Figure 1

Figure 1. Blind, cave-dwelling form of A. mexicanus. By Ltshears (Own work) [Public domain], via Wikimedia Commons.

Members of academia who specialize in eye regression of the blind cave fish, A. mexicanus, have examined several key genes that control how it forages to determine how the genes function on a molecular level. One of the first genes attributed to eye degeneration codes for a protein called Sonic Hedgehog (SHH).

Much like an engineer who wires together components of a functioning computer, SHH is one of the organizing molecules that help specifically wire neurons in the brain during the embryonic stage of development (Menuet et al., 2007). Expansion of SHH signaling results in super-active genes that lead to lens apoptosis (i.e., programmed cell death) and interrupted eye growth (Yamamoto, Stock, Jeffery, 2004). Simply put, the cells of the lens die and the eye ceases to continue developing.

The blind A. mexicanus has been found to express this gene more than their non-blind counterparts, leading scientists to believe that this gene must have a significant role in eye reduction.

In order to test for a correlation, researchers overexpressed SHH to determine the physiological and genetic effects of the gene. It was observed that A. mexicanus with higher amounts of SHH had overall smaller eye-forming structures, such as the retina, lens, and optic cup (Yamamoto, Stock, and Jeffery, 2004). The adult fish were missing eyes  and were unresponsive to light (Yamamoto, Stock, and Jeffery, 2004).

In another study, SHH was also mapped on the genome at varying stages of embryonic development, and it was found that the gene was not transient, but rather well-maintained and spread out to new locations, suggesting that SHH could also be correlated to other factors of brain development that have yet to be explored (Menuet et al., 2007).

The reverse of this process, decrease or inhibition of SHH, was also examined to further confirm correlation. The SHH gene activity was reduced using a drug called Embryos from the A. mexicanus cave-fish were treated with cyclopamine, and these fish had larger eye structures overall (Yamamoto, Stock, and Jeffery, 2004). This supported partial restoration of eye development, however sight was not entirely restored. This is most likely because the cyclopamine was administered either too late or too early into the cave-fish’s embryonic development, minimizing its efficacy (Yamamoto, Stock, and Jeffery, 2004).

More recent research has led studies to focus on a different gene, VAB, which may also explain why the inhibition of SHH did not fully restore eyesight (Yoshizawa et al., 2012). VAB refers to vibration attraction behavior, which allows blind A. mexicanus to sense, locate, and swim towards oscillating objects. VAB is mediated by the number and size of sensory receptors known as cranial superficial neuromasts (SN) in the brain. It is considered an adaptive trait in cave-fish since it improves foraging ability in dim habitats with little food and no large predators (Yoshizawa et al., 2012).

In this particular study, the researchers utilized a genetic analysis of VAB and eye size in blind A. mexicanus whose SN in the eye orbit have been surgically removed, and those with their SN intact (Yoshizawa et al., 2012). It was affirmed that VAB and eye size are strongly correlated with superficial neuromasts located in the eye area, as results showed a significant reduction of VAB when SN were removed.

Figure 2

Figure 2. Correlation among SN, VAB, and eye-size. Red arrows indicate significant positive correlation between traits. Black arrows indicate significant negative correlation between traits (from Yoshizawa et al., 2012)

The genes that control VAB, SN, and eye size were then located and mapped on the complete A. mexicanus genome. It was found that the genome contained 27 linkage groups (LG) containing various genes that could possibly account for VAB, SN, and eye size. Linkage groups refer to groups of genes that act and are inherited as a unit, rather than independently.

These LG were analyzed via quantitative trait locus (QTL) analysis; in this case, meaning that scientists looked at each linkage group to determine which is most likely to be responsible for the three aforementioned traits. The analysis showed a strong correlation between eye loss (eye size) and the VAB sensory system (VAB and SN), supporting the hypothesis that evolution has selected for the VAB sensory system as an adaptive behavior at the expense of eyes (Yoshizawa et al., 2012). This result can be seen as the result of “indirect selection” since eye structures were the trade-off to having the advantage of VAB.

There is a fair amount of evidence supporting the correlation of specific genes to the loss of sight and eye structure entirely in the A. mexicanus. At this point is seems fair to say that sight is a redundant and unnecessary function for these cave-dwelling fish, as they reside in a very dimly-lit environment and they are underwater. One would infer that alternative methods to sensory perception have been developed because blind A. mexicanus with these phenotypes are better adapted to the environment, and more effectively able to forage for food.

Figure 3

Figure 3. A proposed scenario for adaption to cave life mediated by VAB. Droplets of water potentially caused by prey produce ripples and vibrations in the water that blind cave-fish can sense and locate. (from Yoshizawa and Jeffrey, 2011).

However, the actual benefits of eye regression in cave animals have yet to be confirmed. The primary theory is that eye degeneration is metabolically more efficient. It takes a lot of resources to develop and power eyes, as well as put energy towards an alternate method of sight. One might argue that it is just as costly to have eyes and no VAB or SHH, as it is to have VAB or SHH and no eyes. This hypothesis brings us full circle as it brings back the point that, perhaps, the sightless method of vision is a better mechanism than having true eyes. With this in mind, future research has many paths to take and many new questions to answer.

What are the exact metabolic costs of eyes? How do the costs differ from alternative means of sight? Under what conditions are eyes no longer a practical investment? These are important and relevant questions that bring us closer to understanding the complexity of evolution, and potentially to predicting future directions of evolution based on environmental influences.



Chen, James K. et al. “Inhibition of Hedgehog Signaling by Direct Binding of Cyclopamine to Smoothened.” Genes & Development 16.21 (2002): 2743–2748. PMC. Web. 26 Apr. 2017.

Menuet, A., A. Alunni, J.-S. Joly, W. R. Jeffery, and S. Retaux. “Expanded Expression of Sonic Hedgehog in Astyanax Cavefish: Multiple Consequences on Forebrain Development and Evolution.” Development 134.5 (2007): 845-55. Web.

Yoshizawa, Masato, and William R. Jeffrey. A diagrammatic summary of the enhancement of VAB and SN during adaptation of Astyanax to life in caves. Digital image. National Center for Biotechnology Information. U.S. National Library of Medicine, Jan.-Feb. 2011. Web. 27 May 2017.

Yoshizawa, Masato, Yoshiyuki Yamamoto, Kelly E. O’quin, and William R. Jeffery. “Evolution of an Adaptive Behavior and Its Sensory Receptors Promotes Eye Regression in Blind Cavefish.” BMC Biology 10.1 (2012): 108. Web.

Yamamoto, Yoshiyuki, David W. Stock, and William R. Jeffery. “Hedgehog Signalling Controls Eye Degeneration in Blind Cavefish.” Nature 431.7010 (2004): 844-47. Web.

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