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A lysosomal regulatory circuit essential for the development and function of microglia

ABSTRACT: We performed Illumina NovaSeq on zebrafish larvae with or without Zymosan A injection

ORGANISM(S): Danio rerio

PROVIDER: GSE197348 | GEO | 2022/07/15

REPOSITORIES: GEO

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A lysosomal regulatory circuit essential for the development and function of microglia

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A lysosomal regulatory circuit essential for the development and function of microglia

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Lipid-induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders.

Project description:Neuropathic lysosomal storage disorders (LSDs) present with activated pro-inflammatory microglia. However, anti-inflammatory treatment failed to improve disease pathology. We characterise the mechanisms underlying microglia activation in Niemann-Pick disease type A (NPA). We establish that an NPA patient and the acid sphingomyelinase knockout (ASMko) mouse model show amoeboid microglia in neurodegeneration-prone areas. In vivo microglia ablation worsens disease progression in ASMko mice. We demonstrate the coexistence of different microglia phenotypes in ASMko brains that produce cytokines or counteract neuronal death by clearing myelin debris. Overloading microglial lysosomes through myelin debris accumulation and sphingomyelin build-up induces lysosomal damage and cathepsin B extracellular release by lysosomal exocytosis. Inhibition of cathepsin B prevents neuronal death and behavioural anomalies in ASMko mice. Similar microglia phenotypes occur in a Niemann-Pick disease type C mouse model and patient. Our results show a protective function for microglia in LSDs and how this is corrupted by lipid lysosomal overload. Data indicate cathepsin B as a key molecule mediating neurodegeneration, opening research pathways for therapeutic targeting of LSDs and other demyelinating diseases.

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Single-cell RNA sequencing of the cut and uncut caudal fin of zebrafish larvae

Project description:Purpose: The goal of this study was to establish the first detailed cell atlas of the regenerating caudal fin of zebrafish larvae. Intact and regenerating caudal fin were used for single-cell RNA-sequencing with the aim to provide the first integrated model of epimorphic regeneration in zebrafish larvae and demonstrate the diversity of the cells required for blastema formation. Methods: 150 of regenerating caudal fin (cut) and intact caudal fine (uncut) samples were dissociated and loaded into the 10x Genomics Chromium Platform, and sequenced using Illumina NovaSeq 6000. Conclusion: Our study constitutes a resource of the gene expression profile in intact and regenerating caudal fin of zebrafish larvae. We report the application of single-molecule-based sequencing technology for high-throughput profiling of both intact (uncut) and regenerating caudal fin samples (cut) at 24hpA. We confirmed the presence of macrophage subsets, previously described by our group to govern zebrafish fin regeneration, and identified a novel blastemal cell population.

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Transcriptomic Analysis of the Zebrafish Prion Mutants Supports Conserved Cross-Species Function of the Cellular Prion Protein

Project description:Wild-type zebrafish larvae and our prp1ua5003/ua5003;prp2ua5001/ua5001 mutant zebrafish larvae at 3 days post fertilisation were pooled into three biological replicates each of 50 larvae. Each replicate underwent paired end 100-125 and Illumina HiSeq2500 sequencing to a depth of 40 million reads, carried out by Otogenetics (Atlanta, GA). Samples were subsequently processed using the TopHat/Cufflinks bioinformatics pipeline. Alignments were mapped to the zebrafish reference genome, GRCz10. A small amount of wild-type reads were found to contaminate two of the pooled mutant samples and were not included in subsequent analysis. In total there were 1249 genes showing at least a 50% increase (745) in transcript abundance or 50% decrease (504) decrease in transcript abundance in wild-type zebrafish larvae compared to double mutant zebrafish larvae. Subsequent gene ontology analysis shows the biological process showing genes with the biggest decrease in transcript abundance was cell adhesion, and the process with the most genes showing an increase in transcript abundance was Oxidation/Reduction. Our study finds the processes affected by prion knockdown in zebrafish is remarkably similar to other studies in early mice embryos, suggesting a conserved function of the cellular prion protein in the early development of organisms.

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