Subterranean Fishes of the World

3262

2017

AIM 2017

Visual system regression in Astyanax mexicanus cavefish is controlled by multiple genetic factors and eye QTL. The eye QTL on Pachon cavefish chromosome 21 contains the cbsa gene harboring a cis-acting mutation. cbsa encodes cystathionine ß synthase (CBS), the limiting enzyme of the transsulfuration pathway, which catalyzes the conversion of homocysteine to cystathionine, a precursor of cysteine and glutathione. Downregulation of cbsa during the critical period of eye degeneration significantly increases homocysteine concentration and activates expression of the stress related homocysteine-responsive transcription factor ATF3 in cavefish. CBS is also one of the major enzymes responsible for production of H2S, a gaseous signaling factor that functions in vascular system development, and H2S is also decreased in the cavefish embryonic eye. The known role of homocysteine in causing human cardiovascular disease prompted an investigation of the effects of cbsa on development and function of the cavefish vascular system. The vegfaa gene, encoding a VEGF ligand, the flt1 gene, encoding a VEGF receptor, and the Vcam1 gene, encoding a vascular cell adhesion molecule, are coordinately downregulated in the cranial region during cavefish optic degeneration. Angiography using Qdot fluorescent particles showed major leakages in the cavefish eye and brain vasculature frequently leading to hemorrhages. Cavefish hemorrhages are usually reversed within a few days, leaked blood cells are removed, and the afflicted larvae develop into normal adults. Knockdown of the cbsa gene in surface fish induced cranial vascular leakage and hemorrhages resembling those of cavefish. The results suggest that downregulation of cbsa arrests visual system development in cavefish by inducing defects in the cranial vasculature, possibly imposing anoxia and trophic deprivation on the developing eye and optic tectum.

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