Blind cavefish and heat shock protein chaperones: a novel role for hsp90alpha in lens apoptosis

Abstract

Lens apoptosis plays a central role in cavefish eye degeneration. Heat shock proteins (hsps) can regulate apoptosis; therefore, we examined the relationship between constitutive hsp70 and hsp90 expression and lens apoptosis. The model system is Astyanax mexicanus, a teleost species consisting of an eyed surface-dwelling (surface fish) form and numerous blind cavedwelling (cavefish) forms. Optic primordia are formed in the cavefish embryo but they subsequently undergo lens apoptosis, arrest in development and degenerate. Astyanax hsp90 and hsp70 DNAs were isolated to use as probes to compare gene expression during surface fish and cavefish development. Hsp90β β β β β, which encodes one of two hsp90 isoforms, was not expressed in the surface fish or cavefish lens, whereas hsp70 was expressed in the lens of both forms, suggesting that neither is directly involved in lens apoptosis. In contrast, hsp90α α α α α, the other hsp90 isoform, was expressed in the cavefish but not the surface fish lens. Hsp90α α α α α expression peaked shortly before the beginning of lens apoptosis in three convergent cavefish populations, suggesting a close relationship with lens apoptosis. The absence of hsp90β β β β β in the lens allowed us to use geldanamycin and radicicol, specific inhibitors of hsp90 chaperone function, to determine whether lens cell death requires hsp90α α α α α expression. Both inhibitors blocked TUNEL labeling in the cavefish lens, suggesting that hsp90α α α α α is required for apoptosis. In contrast to their effects on the lens, these inhibitors induced TUNEL labeling in the surface epidermis, presumably due to effects on hsp90β β β β β function, implying that the two-hsp90 isoforms may have contrasting roles in cell survival. We conclude that hsp90α α α α α plays a novel role in lens apoptosis and cavefish eye degeneration.

Involvement of Heat Shock Protein (Hsp)90β but Not Hsp90α in Antiapoptotic Effect of CpG-B Oligodeoxynucleotide

“…4, A and C-E), Hooven et al (42) reported that radicicol induced apoptosis by inhibiting the activity of Hsp90␤ in epidermal cells of cavefish. Plausible explanations for the variation in the effect of radicicol on cell viability could be the difference in cell type used (i.e., epidermal cell vs immune cells) or concentrations of radicicol.…”

Developmental mechanisms for retinal degeneration in the blind cavefish Astyanax mexicanus

“…Thus, the degenerating CF lens epithelium proliferates normally, and lens degeneration seems to be due exclusively to apoptosis of fiber cells. Recent data suggest that the heat shock protein chaperone hsp90␣ has a role in this process, although it remains unclear how lens apoptosis is initiated by this molecule (Hooven et al, 2004).…”

The Lens Has a Specific Influence on Optic Nerve and Tectum Development in the Blind Cavefish <i>Astyanax</i>

“…Many of the regressive changes in the cavefi sh eye appear to be related to abnormalities of the lens. Cavefi sh lens fi ber cells do not terminally differentiate, instead they activate the hsp90 ␣ gene and initiate apoptosis [Jeffery and Martasian, 1998;Yamamoto and Jeffery, 2000;Hooven et al, 2004]. Subsequently, the Pax6 gene is downregulated in the corneal epithelium, the anterior eye sector does not differentiate, and retinal growth and photoreceptor cell differentiation are arrested [Yamamoto and Jeffery, 2000], although new cells are still produced in the ciliary marginal zone [Strickler et al, 2002].…”