Genetic mechanism underlying pigmentation, vision and sleep
Melanin is a pigment in animal skins and cuticles. Naturally occurred mutations in genes in melanin synthesis pathways cause condition called albinism across animal kingdom. We and others recently found that gene orthologues of oca2 and slc45a2, the two melanin synthesis genes, express in the nervous system. The mutations of these genes cause sleep and vision phenotype in the fruit fly Drosophila and cavefish (1, 2). Sleep is required for regulating neural activity. Evidence indicates that vision and sleep regulate each other (3-5). Our finding therefore suggests an evolutionary conserved function of pigmentation genes in nervous system. This PhD project, therefore, aims to use the highly genetically editable model, Drosophila, to uncover this novel sleep controlling mechanism by the following objectives.
1) Neural circuits: using scRNA-seq data (1), the student will identify cells enriched with oca2 and slc45a2 in the fly brain. Vertebrate and fly oca2 and slc45a2 transgenes will be reintroduced into these cells and verify if sleep and visual phenotype in oca2 and slc45a2 mutants is reversed. Connectome (6) will then be used to define neural connection between oca2/slc45a2-expressing neurons and the sleep controlling circuits.
2) Neuronal function: oca2 and slc45a2 are predicted to control sleep-related neurotransmission by regulating neuronal pH and Cl- (1). Using fluorescence reporter in brain imaging, the student will verify whether oca2/slc45a2 mutations cause altered pH and Cl- levels.
3) Sleep and vision interaction: to verify if sleep modifies the visual defect in oca2/slc45a2 mutants, the student will perform electroretinogram before and after artificially enhancing the mutants’ sleep by drug feeding or optogenetically activating sleep promoting circuits.