The Fat Gene Cooperates With the Hippo Pathway to Prevent Neuronal Degeneration

Occhi, Simona (2010). The Fat Gene Cooperates With the Hippo Pathway to Prevent Neuronal Degeneration. PhD thesis The Open University.



Fat is a cadherin that regulates planar polarity and acts as a tumor suppressor both in vertebrates and invertebrates. Drosophila fat recessive mutations have been shown to induce an excessive cell proliferation and a hyperplastic tissue overgrowth during larval development.

Fat has recently been described to be part of a signaling cascade, the Hippo tumor suppressor pathway, which regulates organ size and cell proliferation to prevent tumorigenesis.

A further known interactor of Fat is the transcriptional co-factor Atrophin. This connection is highly relevant to neuronal homeostasis, because expansion of polyglutamine tracts in human Atrophins lead to a neurodegenerative disorder, the Dentatorubral-pallidoluysian Atrophy (DRPLA). Microarrays analysis in Drosophila models for DRPLA disorder has shown that fat transcription is downregulated by wt and polyQ mutant Atrophins.

We thus tested the hypothesis that Drosophila Fat is involved in neuronal homeostasis and cell survival. The phenotypic analysis of the Drosophila nervous system in fat mutant fly eyes showed that fat, when mutated, leads to a progressive neurodegenerative phenotype. Interestingly the Hippo Pathway is involved in retinal degeneration and it is partially required for the fat induced phenotype. My morphologic and genetic studies suggest a deregulation of the autophagic signaling in mutants of both Fat and the Hippo pathway as the cell mechanism leading to cell degeneration. In conclusion my data indicate that Fat cooperates with the Hippo Pathway to maintain cellular homeostasis and protect neuronal cells from degeneration.

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