Multifunctional glial support by Semper cells in the Drosophila retina

Abstract

Glial cells play structural and functional roles central to the formation, activity and integrity of neurons throughout the nervous system. In the retina of vertebrates, the high energetic demand of photoreceptors is sustained in part by Müller glia, an intrinsic, atypical radial glia with features common to many glial subtypes. Accessory and support glial cells also exist in invertebrates, but which cells play this function in the insect retina is largely undefined. Using cell-restricted transcriptome analysis, here we show that the ommatidial cone cells (aka Semper cells) in the Drosophila compound eye are enriched for glial regulators and effectors, including signature characteristics of the vertebrate visual system. In addition, cone cell-targeted gene knockdowns demonstrate that such glia-associated factors are required to support the structural and functional integrity of neighboring photoreceptors. Specifically, we show that distinct support functions (neuronal activity, structural integrity and sustained neurotransmission) can be genetically separated in cone cells by down-regulating transcription factors associated with vertebrate gliogenesis (pros/Prox1, Pax2/5/8, and Oli/Olig1,2, respectively). Further, we find that specific factors critical for glial function in other species are also critical in cone cells to support Drosophila photoreceptor activity. These include ion-transport proteins (Na/K+-ATPase, Eaat1, and Kir4.1-related channels) and metabolic homeostatic factors (dLDH and Glut1). These data define genetically distinct glial signatures in cone/Semper cells that regulate their structural, functional and homeostatic interactions with photoreceptor neurons in the compound eye of Drosophila. In addition to providing a new high-throughput model to study neuron-glia interactions, the fly eye will further help elucidate glial conserved "support networks" between invertebrates and vertebrates.

Drosophila glia: Few cell types and many conserved functions

“…The midline glia, which are a small set of specialized wrapping glia in the CNS, as well as the Mesencephalic astrocyte‐derived neurotrophic factor (MANF) expressing cells which might correspond to microglial‐like cells do not express Repo (Halter et al, ; Klaes et al, ; Palgi et al, ; Stratoulias & Heino, ; Walkowicz et al, ; Xiong et al, ). Likewise, the cone cells of the adult Drosophila compound eye, which based on molecular signatures show a remarkable homology to Drosophila and vertebrate glia only transiently express Repo (Charlton‐Perkins, Sendler, Buschbeck, & Cook, ). Thus, some new glial cell types may well be discovered in the future.…”

Genetic control of cellular morphogenesis in Müller glia

“…For instance, from our transcriptome, control and MG genes have similar levels of overlap with zebrafish whole CNS genes (Figure a; Drew et al, ). However, in cross‐species comparisons, we find a highly significant overlap of the MG orthologs with other glial datasets from zebrafish, mice, the fly retina, while the control (mixed retinal population) tissue overlap has no significant difference in the overlap between MG and the whole CNS (Figure a; Roesch et al, ; Qin et al, ; Nelson et al, ; Macosko et al, ; Sifuentes et al, ; Charlton‐Perkins, Sendler, Buschbeck, & Cook, ). Some of these highly conserved genes are known to be involved in glial differentiation.…”

“…Some of these highly conserved genes are known to be involved in glial differentiation. For example, Pax2a (from the Pax2/5/8 family) and the integrins (Itga5, Itga6, and Itgb1a) are expressed in many glial cells, and mutants in all of these genes also resulted in defects in many aspects MG cell morphology (Figure b; Supporting Information Figure S3b–e; Supporting Information Table S4; Supporting Information Figure S3h; Charlton‐Perkins et al, , ; Putaala, Soininen, Kilpeläinen, Wartiovaara, & Tryggvason, ; Quaggin, ; Ambu et al, ; Dzyubenko, Gottschling, & Faissner, ). Remarkably, analysis of the transcriptome of MG cells in pax2a mutants shows that 60% of the genes that affect MG cell morphogenesis in our study have significant changes of expression (Figure c; Supporting Information Table 4).…”

Glial contributions to neuronal health and disease: new insights from Drosophila

“…For example, a recent tour de force analysis, which characterized a large collection of novel in vivo genetic drivers, now offers more comprehensive information about the morphological diversity of glia, as well as cellular interactions in various brain regions, demonstrating, for example, that homotypic and heterotypic repulsion mechanisms maintain glial tiling in the adult CNS (10). In addition, a novel glial cell type (the “Semper” cone cell), which is strikingly similar to vertebrate Muller glia, has been identified in the Drosophila retina (11*) (Figure 1). Both Semper cells and Muller glia radially span the retina and express high levels of crystalline-like proteins to facilitate light scattering throughout retinal tissue.…”

“…Glut1), to support photoreceptor energetics and signaling. Finally, newly published collections of transcriptional profiling experiments employing FACS sorting and in vivo transcript isolation strategies are now providing an unprecedented picture of the genetic profile of glial subtypes in the adult fly brain (11–14). Although glial cell biologists are just beginning to scratch the surface of resolving the varied functional roles of Drosophila glia, it is clear that emerging genetic toolkits and in vivo profiling strategies will rapidly advance our understanding of glial influences on neuronal function and brain health.…”