University of Sussex
Cespedes,_Miguel_Angel.pdf (30.84 MB)

Characterisation of the effects of dioxins on Ahr through its homologue in Drosophila: Spineless

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posted on 2023-06-07, 15:22 authored by Miguel Angel Cespedes
Dioxins are extremely widespread, toxic and persistent pollutants, as well as a major concern for human health. The Aryl hydrocarbon receptor (Ahr) is the key component in the metabolic response to dioxins. Ahr is a cytoplasmic bHLH-PAS transcription factor that, upon binding with dioxin, translocates to the nucleus. There it forms a complex with the Ah receptor nuclear transloator (Arnt), another bHLH-PAS protein, and binds to the eight-nucleotide XRE motif to control gene expression. Previous work with Ahr knock-out mice revealed the existence of dioxin-independent activity for Ahr in development, but the relationship between the two activities of Ahr remains unclear. Our work uses Drosophila to clarify this question, which is central for therapies seeking inactivation of Ahr. The Drosophila Ahr homologue, spineless(ss), does not bind dioxins, however, it physically interacts with Tango (Tgo), Arnt’s fly homologue, and controls gene expression through the XRE motif during development. Here I show that, in the absence of dioxin, Ahr can still bind Tango and Arnt and rescues ss- phenotypes, indicating equivalent dioxin-independent activities. I next demonstrate that exposure to dioxin produces an in vivo hyperactivation of Ahr, which can also be achieved by increasing the dosage of either Tango or Arnt. Thus Ahr shows different levels of activity, from basal to toxic, depending on the presence of specific ligands and cofactors, and the toxic effects of dioxins represent an excess of the Ahr developmental function. I have also carried out a genetic screen in the search of genes that interact with ss. From this screen I have found that the genes that code for the Krüppel-type zinc-finger proteins Squeeze (Sqz) and Rotund (Rn) interact functionally with ss. I demonstrate that Rn and Ss interact physically in vivo. Ahr is also able to interact functionally with rn and sqz indicating that the interaction with zinc-finger proteins might be an ancestral feature of the dioxin receptor.


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