Brain-specific lipoprotein receptors interact with astrocyte derived apolipoprotein and mediate neuron-glia lipid shuttling

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.

The Lipocalin Apolipoprotein D Functional Portrait: A Systematic Review

“…In this respect, the hypothesis of ApoD working on oxidized lipid "whiskers" (Greenberg et al, 2008;Del Caño-Espinel, 2014) on cell membrane bilayers or lipoparticles is appealing and worth contrasting. 6) Recent studies on a Drosophila homolog (Yin et al, 2021) point to lipid droplets as another higher-order lipid structure susceptible to be modulated by ApoD. Searching for lipid droplet-managing functions of vertebrate ApoD is therefore pertinent.…”

Genetic Transsynaptic Techniques for Mapping Neural Circuits in Drosophila

“…Moreover, optogenetic/chemogenetic and calcium imaging techniques have been combined with trans-Tango to understand the functional connectivity between preand postsynaptic neurons (Guo et al, 2018;He et al, 2019;Feng et al, 2020). TRACT has been used to label postsynaptic neurons in olfactory and rhythm circuits (Huang et al, 2017), as well as glial cells (Yin et al, 2021). BAcTrace has been applied to show synaptic connections from olfactory projection neurons to olfactory receptor neurons and Kenyon cells of mushroom bodies and lateral horn neurons (Cachero et al, 2020).…”

Lipophorin receptors regulate mushroom bodies development and participate in learning, memory and sleep in flies

“…The copyright holder for this this version posted November 11, 2021. ; https://doi.org/10.1101/2021.11.10.467940 doi: bioRxiv preprint morphogenesis and function, and future studies should address its interaction with other pathways involved in these processes. [11] shows that a short isoform of LpR1 (LpR1G) interacts with the lipocalin Glaz. Interestingly, a report from the Bellen group shows that the transport of lipids between neurons and glia is mediated by Glaz and neural lazarillo proteins (Nlaz), the orthologs for ApoD in flies [82].…”

“…Moreover, in the case of LpR1, this effect depends on the short isoforms. Specifically, it was reported that knocking down a specific LpR1 short isoform (LpR1G) or LpR2 in LNv reduces activity-dependent dendrite arborization [11,12]. Since a genome-wide RNAi screen in cultured neurons from D. melanogaster embryos identified LpR2 as a gene implicated in neuronal development [13] and given the fact that LpR1 and LpR2 are widely expressed in the Drosophila larval brain [11,12], it is possible to propose that LpRs could contribute to the development, maturation and operation of several fly brain regions.…”

“…Thus, the isoforms transcribed from the proximal promoter are also known as the "short" ones, while those transcribed from the distal promoter are known as the "long" isoforms [6,9,11].…”