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

Abstract

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

“…However, we did not observe phenotypic effect in a control line in which Dicer2 protein was expressed alone, which indicates that the changes were related to the DmMANF deficiency. Interestingly, our other studies showed that overexpression of DmMANF in astrocyte-like glia results in abnormal arborisation of PDF-expressing neurons (Walkowicz et al, 2021). The finding rises the question of whether the morphological changes of PDFpositive neurons are related to disturbances in the expression of DmMANF specifically in tim-positive glia.…”

“…Interestingly, our other studies showed that overexpression of DmMANF in astrocyte-like glia results in abnormal arborisation of PDF-expressing neurons ( Walkowicz et al, 2021 ). The finding rises the question of whether the morphological changes of PDF-positive neurons are related to disturbances in the expression of DmMANF specifically in tim -positive glia.…”

“…Here, we have shown that another neurotrophic factor, DmMANF, which has been detected in Drosophil a ( Palgi et al, 2009 ), is involved in the regulation of the circadian clock. In the brain of adult flies DmMANF is present in both neurons and glia ( Stratoulias and Heino, 2015a ), reaching particularly high levels in epithelial glial cells of the lamina ( Walkowicz et al, 2017 ) and in two types of the medulla glia: astrocyte-like glia (AlGl) and ensheathing glia (EnGl) ( Krzeptowski et al, 2018 ; Walkowicz et al, 2021 ). Both AlGl and EnGl express the core clock protein PERIOD (PER) and these glial subtypes have already been described as glial peripheral oscillators ( Górska-Andrzejak et al, 2018 ; Krzeptowski et al, 2018 ).…”

“…In the brain of adult flies, DmMANF is expressed in glial cells and neurons (Stratoulias and Heino, 2015a;Walkowicz et al, 2017Walkowicz et al, , 2021. However, approximately 50% of this protein seems to be concentrated in the retina (Supplementary Figure 1).…”

Special issue editorial: Glial plasticity in health and disease

“…Glial cells contribute to circadian rhythms and regulating the behavior of flies ( Drosophila melanogaster ). Walkowicz and colleagues show that ensheathing‐ and astrocyte‐like glia in flies utilize mesencephalic astrocyte‐derived neurotrophic factor (DmMANF, an evolutionarily conserved ortholog of mammalian MANF) to regulate sleep and circadian rhythms (Walkowicz et al, 2021). Furthermore, they find that DmMANF regulates the circadian rhythms of the Na + /K + ‐ATPase α‐subunit within glia themselves.…”