Meeting Abstract
The absence of eyes is a hallmark of cave adapted animals. In the teleost Astyanax mexicanus, eyeless cavefish (CF) have evolved several times from eyed surface fish (SF) ancestors. CF embryos initiate eye development but eyes stop growing and degenerate in larvae. Despite decades of genetic analysis in Astyanax, the mutated genes controlling the eyeless phenotype are still unknown. Here we identify the cbsa gene, which is downregulated in the developing CF eye, located in an eye QTL, and harbors a cis-acting regulatory mutation. The cbsa gene encodes cystathionine beta-synthase, the limiting enzyme of the transsulfuration pathway, which converts homocysteine (hCys) to cystathionine, the precursor of glutathione. We found that hCys concentration is elevated in CF embryos and injection of hCys into eggs causes eye loss in SF embryos. High levels of hCys are known to affect the cardiovascular system. Accordingly, angiography revealed leakages in CF eye vasculature leading to blood hemorrhages, which were not observed in SF. The hemorrhages are repaired within a few days, leaked blood cells are removed by macrophages, and the afflicted CF larva develop into normal adults. Knockdown of cbsa in SF induced eye loss, blood vasculature defects, and hemorrhages resembling CF. Regulatory mutations leading to cbsa downregulation, elevated hCys levels, and dysfunctional optic vasculature were observed in multiple Astyanax CF populations. We conclude that eye loss evolved repeatedly by mutations in the cbsa gene and hCys mediated defects in optic blood vasculature, which inhibit growth by imposing anoxia and trophic deprivation on the developing CF eye.
