The significance of DAF-16 and its role in the phenotypic covariance of longevity, immunity and stress resistance in the Caenorhabditis nematodes

Gandhi, Francis Amrit Raj (2010). The significance of DAF-16 and its role in the phenotypic covariance of longevity, immunity and stress resistance in the Caenorhabditis nematodes. University of Birmingham. Ph.D.

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Abstract

Ageing, immunity and stress tolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin–like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. In this project we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four Caenorhabditis species. We show, using phenotypic analysis of DAF-16 influenced phenotypes, that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (Caenorhabditis elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Quantitative Real-Time PCR, which positively correlate with the observed phenotypes. We also provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis. Finally, we take a closer look at the daf-16 gene and its isoforms in C. elegans and their role in driving specific responses to stress. These findings impact upon our understanding of the diversification of the IIS pathway and the evolution of longevity in general, and illustrate how such differences could explain both inter and intra-species differences in ageing, immunity and stress response.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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