Abstract
Invertebrate glia performs most of the key functions controlled by mammalian glia in the nervous system and provides an ideal model for genetic studies of glial functions. To study the influence of adult glial cells in ageing we have performed a genetic screen in Drosophila using a collection of transgenic lines providing conditional expression of micro-RNAs (miRNAs). Here, we describe a methodological algorithm to identify and rank genes that are candidate to be targeted by miRNAs that shorten lifespan when expressed in adult glia. We have used four different databases for miRNA target prediction in Drosophila but find little agreement between them, overall. However, top candidate gene analysis shows potential to identify essential genes involved in adult glial functions. One example from our top candidates' analysis is gartenzwerg ( garz). We establish that garz is necessary in many glial cell types, that it affects motor behaviour and, at the sub-cellular level, is responsible for defects in cellular membranes, autophagy and mitochondria quality control. We also verify the remarkable conservation of functions between garz and its mammalian orthologue, GBF1, validating the use of Drosophila as an alternative 3Rs-beneficial model to knock-out mice for studying the biology of GBF1, potentially involved in human neurodegenerative diseases.
Highlights
Despite the fact that glial cells were initially identified as the connective tissue of the brain[1], work developed in the past decades has shed a light on a much more intricate role for these cells in developing and maintaining nervous system homeostasis
To rank target genes within each database taking into account both the likelihood of being targeted by a given miRNA and the strength of the effect of this miRNA in adult glia, we first multiplied the average strength of each miRNA from our screen by the strength of the target prediction (Score) given by the database, obtaining the parameter (Score)*Av(χ2)
This was done for all miRNAs tested in our screen that were present in each database
Summary
Despite the fact that glial cells were initially identified as the connective tissue of the brain[1], work developed in the past decades has shed a light on a much more intricate role for these cells in developing and maintaining nervous system homeostasis (reviewed in 2). Several studies have been taking advantage of Drosophila’s powerful genetic manipulation to better understand the role of glia in the development and maintenance of the nervous system (see 8 for review). Popular animal models for studying glial functions are zebrafish, which provide a useful platform for tissue and cell biology, with some capability for genetic manipulation[9] and genetically modified mice[10]. Despite having a different developmental origin, glial cells have converged in Drosophila and mammals towards the same key functions of neurotransmission regulation, insulation and immune surveillance/phagocytosis[8], making the fruit-fly an organism of choice for studying the function of glial cells
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