Abstract
Lipid shuttling between neurons and glia contributes to the development, function, and stress responses of the nervous system. To understand how a neuron acquires its lipid supply from specific lipoproteins and their receptors, we perform combined genetic, transcriptome, and biochemical analyses in the developing Drosophila larval brain. Here we report, the astrocyte-derived secreted lipocalin Glial Lazarillo (GLaz), a homolog of human Apolipoprotein D (APOD), and its neuronal receptor, the brain-specific short isoforms of Drosophila lipophorin receptor 1 (LpR1-short), cooperatively mediate neuron-glia lipid shuttling and support dendrite morphogenesis. The isoform specificity of LpR1 defines its distribution, binding partners, and ability to support proper dendrite growth and synaptic connectivity. By demonstrating physical and functional interactions between GLaz/APOD and LpR1, we elucidate molecular pathways mediating lipid trafficking in the fly brain, and provide in vivo evidence indicating isoform-specific expression of lipoprotein receptors as a key mechanism for regulating cell-type specific lipid recruitment.
Highlights
Lipid shuttling between neurons and glia contributes to the development, function, and stress responses of the nervous system
To determine how neuronal lipoprotein receptors mediate lipid uptake, based on findings from previous studies, we focus our genetic and functional analyses on the Drosophila LpR1 gene, which expresses in the larval central nervous system (CNS) and is required for LNvs’ dendrite development and synaptic functions[36]
Using the developing Drosophila larval brain as a model, we investigate how neurons acquire their lipid supply from neighboring astrocytes and the regulatory mechanisms associated with the neuronglia lipid trafficking
Summary
Lipid shuttling between neurons and glia contributes to the development, function, and stress responses of the nervous system. Apolipoproteins are among the most abundant secretory factors that are produced and released by mammalian astrocytes[6,7], a group of glial cells with complex morphology and highly branched structures that are intimately associated with synapses[6,8], suggesting a critical role for gliaderived lipoprotein and their lipid cargos in synapse formation and function[2,9] This notion is supported by studies in cultured mammalian CNS neurons, where glia-derived cholesterol and phospholipids are essential for synaptogenesis[9,10,11]. Recent findings in the Drosophila system indicate essential functions of glia in synapse formation and neurotransmission[12,13,14,15], the link between neuron-glia lipid transport and synaptic function has yet to be established Characterized by their high metabolic rate and elaborate morphology, neurons require a continuous lipid supply throughout their lifetime. Observations made in the mammalian system provided evidence illustrating fatty acid (FA) transport into astrocytes mediated by ApoE and the importance of neuronal lipid clearance[31,32]
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