Glial expression of DmMANF is required for the regulation of activity, sleep and circadian rhythms in the visual system of Drosophila melanogaster.

DmMANF, Drosophila melanogaster mesencephalic astrocyte-derived neurotrophic factor (DmMANF) is an evolutionarily conserved orthologue of mammalian MANF. This neurotrophic factor exerts many functions in the Drosophila brain, particularly those dependent on glial cells. As we found in our earlier study, downregulation of DmMANF in glia induces degeneration of glial cells in the first optic neuropil (lamina) where DmMANF abundance is especially high. In the present study, we observed that changes in the level of DmMANF in two types of glia, astrocyte-like glia (AlGl) and ensheathing glia (EnGl), affect activity and sleep of flies. Interestingly, a proper level of DmMANF in AlGl seems to be important in guiding processes of pigment dispersing factor (PDF)-expressing clock neurons. This is supported by our finding that DmMANF overexpression in AlGl leads to structural changes in the architecture of the PDF-positive arborization in the brain. Finally, we detected that DmMANF also affects rhythms in glia themselves, as circadian oscillations in expression of the catalytic α subunit of the sodium pump in the lamina epithelial glia were abolished after DmMANF silencing. DmMANF expressed in AlGl and EnGl seems to affect the activity of neurons leading to changes in behaviour.

Mesencephalic Astrocyte-Derived Neurotrophic Factor Regulates Morphology of Pigment-Dispersing Factor-Positive Clock Neurons and Circadian Neuronal Plasticity in Drosophila melanogaster.

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is one of a few neurotrophic factors described in Drosophila melanogaster (DmMANF) but its function is still poorly characterized. In the present study we found that DmMANF is expressed in different clusters of clock neurons. In particular, the PDF-positive large (l-LNv) and small (s-LNv) ventral lateral neurons, the CRYPTOCHROME-positive dorsal lateral neurons (LNd), the group 1 dorsal neurons posterior (DN1p) and different tim-positive cells in the fly's visual system. Importantly, DmMANF expression in the ventral lateral neurons is not controlled by the clock nor it affects its molecular mechanism. However, silencing DmMANF expression in clock neurons affects the rhythm of locomotor activity in light:dark and constant darkness conditions. Such phenotypes correlate with abnormal morphology of the dorsal projections of the s-LNv and with reduced arborizations of the l-LNv in the medulla of the optic lobe. Additionally, we show that DmMANF is important for normal morphology of the L2 interneurons in the visual system and for the circadian rhythm in the topology of their dendritic tree. Our results indicate that DmMANF is important not only for the development of neurites but also for maintaining circadian plasticity of neurons.