Granulins Regulate Aging Kinetics in the Adult Zebrafish Telencephalon

Abstract

Granulins (GRN) are secreted factors that promote neuronal survival and regulate inflammation in various pathological conditions. However, their roles in physiological conditions in the brain remain poorly understood. To address this knowledge gap, we analysed the telencephalon in Grn-deficient zebrafish and identified morphological and transcriptional changes in microglial cells, indicative of a pro-inflammatory phenotype in the absence of any insult. Unexpectedly, activated mutant microglia shared part of their transcriptional signature with aged human microglia. Furthermore, transcriptome profiles of the entire telencephali isolated from young Grn-deficient animals showed remarkable similarities with the profiles of the telencephali isolated from aged wildtype animals. Additionally, 50% of differentially regulated genes during aging were regulated in the telencephalon of young Grn-deficient animals compared to their wildtype littermates. Importantly, the telencephalon transcriptome in young Grn-deficent animals changed only mildly with aging, further suggesting premature aging of Grn-deficient brain. Indeed, Grn loss led to decreased neurogenesis and oligodendrogenesis, and to shortening of telomeres at young ages, to an extent comparable to that observed during aging. Altogether, our data demonstrate a role of Grn in regulating aging kinetics in the zebrafish telencephalon, thus providing a valuable tool for the development of new therapeutic approaches to treat age-associated pathologies.

A zebrafish model of Granulin deficiency reveals essential roles in myeloid cell differentiation

“…This aberrant production of inflammatory genes in the absence of grna indicates a dysregulated inflammatory response, which is consistent with previous reports in mice lacking Grn (Yin et al, 2010) and our previous data showing morphological and transcriptional changes in microglial cells, the resident macrophages of the brain, in zebrafish lacking grna and grnb, indicative of a pro-inflammatory phenotype (Zambusi et al, 2020). These observations also support functional conservation between the mammalian granulin and the zebrafish orthologue grna.…”

“…In the last years, multiple lines of evidence reveal the impact of microglia in neurological disorders (Bachiller et al, 2018;Heneka, 2019). The production of aberrant microglia in the absence of granulin has also been described recently in the adult zebrafish (Zambusi et al, 2020) Among the complex regulatory network of TFs that regulate hematopoiesis, GATA1 and PU.1 are key on regulating the erythroid versus myeloid program by antagonizing each other (Iwasaki & Akashi, 2007;Monteiro et al, 2011;Wolff & Humeniuk, 2013;Zhang et al, 2000).…”

Innate Immune Pathways Promote Oligodendrocyte Progenitor Cell Recruitment to the Injury Site in Adult Zebrafish Brain

“…In order to understand the regulatory mechanisms of accumulation of Olig2:GFP + cells downstream of innate immunity pathways after skull injury, we analyzed the injuryinduced transcriptomic changes in Olig2:dsRed + cells (enriched for OPCs [82]) acutely isolated from the injured zebrafish telencephalon 3 days after either vehicle or inhibitor treatment. We observed 1649 significantly regulated transcripts in dsRed + cells after injury in vehicle-treated brains compared with intact brains (Figure S7A).…”

Aging Activates the Immune System and Alters the Regenerative Capacity in the Zebrafish Heart

“…Interestingly, a similar observation has been made in zebrafish for microglia, which are the macrophages of the brain. Microglia cells in the adult zebrafish telencephalon display larger cell bodies and shorter processes with aging [56]. As macrophages are phagocytic active cells, resident macrophages in the zebrafish heart are likely to play a role in removing debris.…”