Abstract
Compromised heat shock protein 90 (Hsp90) function reveals cryptic phenotypes in flies and plants. These observations were interpreted to suggest that this molecular stress-response chaperone has a capacity to buffer underlying genetic variation. Conversely, the protective role of Hsp90 could account for the variable penetrance or severity of some heritable developmental malformations in vertebrates. Using zebrafish as a model, we defined Hsp90 inhibitor levels that did not induce a heat shock response or perturb phenotype in wild-type strains. Under these conditions the severity of the recessive eye phenotype in sunrise, caused by a pax6b mutation, was increased, while in dreumes, caused by a sufu mutation, it was decreased. In another strain, a previously unobserved spectrum of severe structural eye malformations, reminiscent of anophthalmia, microphthalmia, and nanophthalmia complex in humans, was uncovered by this limited inhibition of Hsp90 function. Inbreeding of offspring from selected unaffected carrier parents led to significantly elevated malformation frequencies and revealed the oligogenic nature of this phenotype. Unlike in Drosophila, Hsp90 inhibition can decrease developmental stability in zebrafish, as indicated by increased asymmetric presentation of anophthalmia, microphthalmia, and nanophthalmia and sunrise phenotypes. Analysis of the sunrise pax6b mutation suggests a molecular mechanism for the buffering of mutations by Hsp90. The zebrafish studies imply that mild perturbation of Hsp90 function at critical developmental stages may underpin the variable penetrance and expressivity of many developmental anomalies where the interaction between genotype and environment plays a major role.
Highlights
Human malformations frequently show no clear Mendelian inheritance pattern, even when familial recurrence suggests a strong underlying genetic component
Unilateral malformations in paired organs, such as the failure of an eye to develop on one side only, remind us that gene function is often modified by environmental factors
Earlier work suggested involvement of chaperone proteins like heat shock protein 90 (Hsp90), which assist with normal protein folding during development and work overtime to keep proteins functional in response to environmental stress
Summary
Human malformations frequently show no clear Mendelian inheritance pattern, even when familial recurrence suggests a strong underlying genetic component. It has become clear that robustness of the wild-type (WT) phenotype to extensive genetic and environmental variation may be ascribed to the complexity, and strong buffering capacity of gene networks and cellular surveillance mechanisms [3,4]. These homeostatic systems are of major clinical relevance as potential prophylactic and therapeutic targets. Understanding the molecular events that can alter the balance between cryptic and overt phenotypes is an important endeavour
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