Mutants of the white ABCG Transporter in Drosophila melanogaster Have Deficient Olfactory Learning and Cholesterol Homeostasis.

Jennifer L Myers,Nicholas Narwold,Gregg Roman,Krishna Bhat,Maria Porter,Brigitte Dauwalder

doi:10.3390/ijms222312967

Abstract

Drosophila’s white gene encodes an ATP-binding cassette G-subfamily (ABCG) half-transporter. White is closely related to mammalian ABCG family members that function in cholesterol efflux. Mutants of white have several behavioral phenotypes that are independent of visual defects. This study characterizes a novel defect of white mutants in the acquisition of olfactory memory using the aversive olfactory conditioning paradigm. The w1118 mutants learned slower than wildtype controls, yet with additional training, they reached wildtype levels of performance. The w1118 learning phenotype is also found in the wapricot and wcoral alleles, is dominant, and is rescued by genomic white and mini-white transgenes. Reducing dietary cholesterol strongly impaired olfactory learning for wildtype controls, while w1118 mutants were resistant to this deficit. The w1118 mutants displayed higher levels of cholesterol and cholesterol esters than wildtype under this low-cholesterol diet. Increasing levels of serotonin, dopamine, or both in the white mutants significantly improved w1118 learning. However, serotonin levels were not lower in the heads of the w1118 mutants than in wildtype controls. There were also no significant differences found in synapse numbers within the w1118 brain. We propose that the w1118 learning defect may be due to inefficient biogenic amine signaling brought about by altered cholesterol homeostasis.

Highlights

Drosophila’s white gene, necessary for normal eye pigmentation, has one of the longest and most impactful histories of any gene [1,2,3]
We demonstrate a role for the white gene in olfactory associative learning, and we explore possible mechanisms related to cholesterol homeostasis
It is interesting that the slow learning phenotype of w1118 mutants was not present under these sterol restrictive diets. These results suggest that cholesterol homeostasis is altered in w1118 mutants in a manner that changes the optimal level of dietary cholesterol for learning and perhaps other cholesterol-dependent phenotypes

Summary

Introduction

Drosophila’s white gene, necessary for normal eye pigmentation, has one of the longest and most impactful histories of any gene [1,2,3]. Loss-of-function white alleles are commonly found in Drosophila experimental genotypes [4,5]. Despite the usefulness of these observable genetic markers, the presence of white mutant alleles can pose a confounding problem in many experiments because they have pleiotropic behavioral and neural phenotypes, including aspects of learning and memory. The molecular mechanisms by which the mutant white alleles produce these non-visual phenotypes remain mostly uncertain. Some ABC transporters, like white in the pigment granules of the Drosophila eye and Malpighian tubules, are involved in transport from the cytoplasm into intracellular compartments [22]. The ABC G-subfamily (ABCG), which includes the white protein, is distinctive because it consists entirely of half transporters that form obligate homo- or heterodimers for function [26,27]

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Conclusion