The secreted neurotrophin Spätzle 3 promotes glial morphogenesis and supports neuronal survival and function

Abstract

Most glial functions depend on establishing intimate morphological relationships with neurons. Significant progress has been made in understanding neuron-glia signaling at synaptic and axonal contacts, but how glia support neuronal cell bodies is unclear. Here we explored the growth and functions of cortex glia (which associate almost exclusively with neuronal cell bodies) to understand glia-soma interactions. We show that cortex glia tile with one another and with astrocytes to establish unique central nervous system (CNS) spatial domains that actively restrict glial growth, and selective ablation of cortex glia causes animal lethality. In an RNAi-based screen, we identified αSNAP (soluble NSF [N-ethylmalemeide-sensitive factor] attachment protein α) and several components of vesicle fusion and recycling machinery as essential for the maintenance of cortex glial morphology and continued contact with neurons. Interestingly, loss of the secreted neurotrophin Spätzle 3 (Spz3) phenocopied αSNAP phenotypes, which included loss of glial ensheathment of neuron cell bodies, increased neuronal cell death, and defects in animal behavior. Rescue experiments suggest that Spz3 can exert these effects only over very short distances. This work identifies essential roles for glial ensheathment of neuronal cell bodies in CNS homeostasis as well as Spz3 as a novel signaling factor required for maintenance of cortex glial morphology and neuron-glia contact.

Drosophila ClC‐a is required in glia of the stem cell niche for proper neurogenesis and wiring of neural circuits

“…Additional experiments indicated that ClC‐a + nuclei present on the surface of the CB and in cortical areas belonged to cortex glia. The membrane and nuclear patterns of ClC‐a + cells were consistent with the nuclear patterns and the membrane scaffold, also known as the trophospongium (Hoyle, Williams, & Phillips, ), observed with the recently described cortex glia driver wrapper (Coutinho‐Budd et al, ) (compare Figure g with Figure l). In fact, there was extensive colocalization between ClC‐a + and wrapper + membranes in the CB and OL (Figure m,n), including surface‐associated cortex glia on the OPC (Figure n,n'').…”

Drosophila glia: Few cell types and many conserved functions

“…Proliferation is likely to occur during larval stages, as determined by an increase in nuclear counts, and is in part regulated by FGF‐receptor Heartless (Htl) and Insulin receptor signaling but not via the PI3K/TOR pathway (Avet‐Rochex et al, ). During metamorphosis cortex glial cells remain and stay into adulthood (Coutinho‐Budd, Sheehan, & Freeman, ). In abdominal neuromeres of the ventral nerve cord of third instar larvae, single cortex glial cells engulf the entire lineage of a neural stem cell comprising on average 55 neurons (Coutinho‐Budd et al, ; Dumstrei, Wang, & Hartenstein, ; Pereanu et al, ; Spéder & Brand, ).…”

“…As development proceeds, these glial cells extend processes around the stem cells as well as their progeny to establish non‐overlapping spatial domains. The growth of cortex glial cells is limited by astrocyte‐like glial cells encasing the neuropil (Coutinho‐Budd et al, ). Tiling and growth of cortex glial cells requires several components of the vesicle fusion and recycling machinery and the cell autonomous action of the secreted neurotrophin Spätzle 3 (Coutinho‐Budd et al, ).…”

“…The growth of cortex glial cells is limited by astrocyte‐like glial cells encasing the neuropil (Coutinho‐Budd et al, ). Tiling and growth of cortex glial cells requires several components of the vesicle fusion and recycling machinery and the cell autonomous action of the secreted neurotrophin Spätzle 3 (Coutinho‐Budd et al, ). Moreover, it has been shown that growth of cortex glial cells is modulated by the metabolic state of the animal and is induced by nutrition‐induced activation of PI3K/Akt (Spéder & Brand, ).…”

“…They show a pronounced tiling behavior with only very few overlapping territories. Exuberating growth appears to be restricted by glial–glial interactions (Coutinho‐Budd et al, ; Stork et al, ). Astrocyte‐like glial cells in Drosophila are electrically coupled as their mammalian counterparts and Ca 2+ waves can be detected (Ma et al, ; MacNamee et al, ).…”