Axonal wrapping in theDrosophilaPNS is controlled by glia-derived neuregulin homolog Vein

Abstract

Efficient neuronal conductance requires that axons are insulated by glial cells. For this, glial membranes need to wrap around axons. Invertebrates show a relatively simple extension of glial membranes around the axons, resembling Remak fibers formed by Schwann cells in the mammalian peripheral nervous system. To unravel the molecular pathways underlying differentiation of glial cells that provide axonal wrapping, we are using the genetically amenable Drosophila model. At the end of larval life, the wrapping glia differentiates into very large cells, spanning more than 1 mm of axonal length. The extension around axonal membranes is not influenced by the caliber of the axon or its modality. Using cell typespecific gene knockdown we show that the extension of glial membranes around the axons is regulated by an autocrine activation of the EGF receptor through the neuregulin homolog Vein. This resembles the molecular mechanism employed during cell-autonomous reactivation of glial differentiation after injury in mammals. We further demonstrate that Vein, produced by the wrapping glia, also regulates the formation of septate junctions in the abutting subperineurial glia. Moreover, the wrapping glia indirectly controls the proliferation of the perineurial glia. Thus, the wrapping glia appears center stage to orchestrate the development of the different glial cell layers in a peripheral nerve.

Unwrapping the unappreciated: recent progress in Remak Schwann cell biology

“…In peripheral nerves, Drosophila wrapping glia ensheath and separate single or small bundles of axons with their membranes within the nerve, similar to the segregation of individual axons by RSCs [43,44]. Recent work suggests that several genes implicated in RSC development, including NRG1 [45] and Laminin [30,46], appear to perform analogous functions, and act through similar molecular mechanisms in Drosophila wrapping glia. Thus, one possible avenue for further exploration into basic RSC biology might be comparative analyses with wrapping glia in Drosophila .…”

Drosophila glia: Few cell types and many conserved functions

“…They proliferate by symmetric cell division during all larval stages until a final round of proliferation at late wandering or early pupal stage (Avet‐Rochex, Kaul, Gatt, McNeill, & Bateman, ; Awasaki et al, ; Colonques, Ceron, & Tejedor, ; Omoto, Lovick, & Hartenstein, ; Pereanu, Shy, & Hartenstein, ; Subramanian et al, ). In some cases perineurial glial cells can give rise to other glial cells, such as wrapping glia, and thus may constitute a pool of multipotent glial progenitors (Bauke, Sasse, Matzat, & Klämbt, ; Edwards, Nuschke, Nern, & Meinertzhagen, ; Franzdóttir et al, ).…”

“…In addition, perineurial glial growth is affected by a putative neurotransmitter transporter ( ine, inebriated ); a potassium channel ( eag, ether a go–go ), a Calmodulin‐binding E3 ubiquitin ligase ( poe, purity of essence ), a putative neuropeptide related to the pituitary adenylate cyclase activator peptide ( amn, amnesiac ), and the Drosophila orthologue of the human Type 1 neurofibromatosis gene NF1 (Yager et al, ). These genes might act rather indirectly on perineurial growth since as soon as a nerve becomes bigger in size more perineurial glial cells are formed (Matzat et al, ). Thus, one could speculate that the cell‐size of individual perineurial glial cells is genetically fixed, which may be linked to its role in metabolic homeostasis of the nervous system.…”

“…Wrapping glial cells of the abdominal nerves do not divide during larval stages and grow to an enourmous size. Since only three to four wrapping glial cells cover one entire nerve, these cells have to wrap the up to 3 mm long axon segments found in the third instar larva (von Hilchen et al, ; Matzat et al, ). It is presently still unclear how wrapping glial fate is specified but some of the transcription factors required for its differentiation have been identified ((Bauke et al, ), see below).…”

Differentiation of Drosophila glial cells

“…Glial cells that cease their migration start to differentiate (Figure ). This has been analyzed for peripheral wrapping glial cells . These cells behave similar to nonmyelinating Schwann cells forming the so‐called Remak fibers of vertebrates .…”