Gene expression profiling reveals a conserved microglia signature in larval zebrafish

Abstract

Microglia are the resident macrophages of the brain. Over the past decade, our understanding of the function of these cells has significantly improved. Microglia do not only play important roles in the healthy brain but are involved in almost every brain pathology. Gene expression profiling allowed to distinguish microglia from other macrophages and revealed that the full microglia signature can only be observed in vivo. Thus, animal models are irreplaceable to understand the function of these cells. One of the popular models to study microglia is the zebrafish larva. Due to their optical transparency and genetic accessibility, zebrafish larvae have been employed to understand a variety of microglia functions in the living brain. Here, we performed RNA sequencing of larval zebrafish microglia at different developmental time points: 3, 5, and 7 days post fertilization (dpf). Our analysis reveals that larval zebrafish microglia rapidly acquire the core microglia signature and many typical microglia genes are expressed from 3 dpf onwards. The majority of changes in gene expression happened between 3 and 5 dpf, suggesting that differentiation mainly takes place during these days. Furthermore, we compared the larval microglia transcriptome to published data sets of adult zebrafish microglia, mouse microglia, and human microglia. Larval microglia shared a significant number of expressed genes with their adult counterparts in zebrafish as well as with mouse and human microglia. In conclusion, our results show that larval zebrafish microglia mature rapidly and express the core microglia gene signature that seems to be conserved across species.

Role of Macrophages and Microglia in Zebrafish Regeneration

“…Easy manipulation and visualization of optically translucent zebrafish embryos allow for real-time imaging of microglial activity. Markers for macrophages in live imaging zebrafish studies include transgene promoter mpeg1 and mfap4, similar to their mammalian counterpart studies [ 87 , 185 ]; however, microglial markers in zebrafish differ slightly from mammalian markers and include myeloid marker lymphocyte cytosolic plastin 1 (lcp1) and 4C4 [ 72 , 90 , 186 ]. It is important to note that the diversity of macrophages and microglial subtypes in zebrafish is an emerging area of study, and there is not unanimous agreement on reliable markers for each cell type.…”

Repression of lysosomal transcription factors Tfeb and Tfe3 is essential for the migration and function of microglia

“…Finally, our experiments reveal that Tfeb and Tfe3 must be repressed for early development of microglia, but it is unclear why hyperactivation of Tfeb and Tfe3 leads to migration defects in microglia. In addition, much less is known about the regulation of these transcription factors in the maintenance and function of adult microglia (Ferrero et al, 2018;Mazzolini et al, 2019;Xu et al, 2015). Future studies aiming to understand the regulation and functions of Tfeb and Tfe3 in microglia during development and aging will not only broaden our understanding of lysosomal pathways in these essential glial cells, but will also inform therapeutic strategies aimed at modulating Tfeb activity in neurodegeneration and other diseases.…”

Alarm Test: A Novel Chemical-Free Behavioural Assessment Tool for Zebrafish

“…While ZFs can be used for modelling liver cancer [11], diabetes [12,13], cardiovascular disorders [14,15] and other metabolic disorders [16,17], the major contribution of this model is projected in neurodegenerative sciences. This is due to the extensive similarity of its brain structure with that of the humans [18,19]. The incidences of neurodegenerative diseases in the growing population have increased worldwide, and it is expected that its prevalence will rise in the next few years.…”