Drosophila orthologues of oculocutaneous albinism-associated genes regulate sleep and circadian rhythm via visual neurotransmission

Abstract

Melanin is a pigment found in the skin and cuticle of animals. Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders defined by reduced melanin in skin and eyes, and is associated with visual defects such as foveal hypoplasia and infantile nystagmus. Sleep disturbance has been documented in children with OCA, and oca2 loss-of-function in cavefish causes constitutive sleep loss, indicating a sleep regulatory function of OCA-associated genes in the visual system. To test potential roles of OCA-associated genes in regulating sleep and vision through evolutionarily conserved mechanisms, we used Drosophila melanogaster, a high-throughput phenotyping system to screen sleep and visual phenotypes for genetic mutants of OCA-associated genes. Among the OCA-associated genes, bidirectional DRSC Integrative Ortholog Prediction Tool identified Drosophila orthologues for OCA2, SLC45A2, SLC24A5 and LRMDA. RNAi-mediated knockdown in developing Drosophila eye tissue identified the OCA2 orthologues hoe1, hoe2, and the SLC45A2 orthologue lovit as candidate genes required for normal sleep. Moreover, hoe1, hoe2 and lovit1 null alleles reduced sleep and circadian rhythmicity, and showed altered photoreceptor neurotransmission. Consistently, the enhancer-trap reporter assay and scRNA dataset revealed that these OCA orthologues express in brain regions critical for sleep and vision regulation. Collectively the data indicate evolutionarily conserved neuronal function of OCA2 and SLC45A2 orthologues that regulate sleep and photoreceptor neurotransmission. Significance StatementOculocutaneous albinism (OCA) is a pigmentation disorder of the skin and eyes accompanied by reduced visual acuity. Children with albinism also report sleep disturbance, and the mechanism is unclear. We tested whether genes mutated in albinism regulate sleep in the fruit fly Drosophila melanogaster, an organism that has a divergent melanin synthesis pathway and lacks tyrosinase, the principal pigmentation enzyme in mammals. We found Drosophila OCA orthologues, hoe1, hoe2 and lovit express widely in the nervous system and control sleep, circadian rhythmicity and neural activity of photoreceptors. Importantly no pigmentation defects were detected in aforementioned mutants, our finding is consistent with the proposal that pleiotropic neuronal function of OCA2 and SLC45A2 underlies the sleep and vision symptoms in albinism.