Immature cortex glia sit atop the OPC and send extrinsic cues to set the balance between neuroepithelial expansion and neuroblast transition. function. Finally, Proteasome-IN-1 we will highlight how these early developmental roles of glia contribute to nervous system dysfunction in neurodevelopmental and neurodegenerative disorders. (Homem and Knoblich, 2012). Accordingly, glial cells form an important component of the NSC niche that regulates neurogenesis (Doe, 2017). This has been well-studied within the visual system, which arises from a specialized neuroepithelium during development called the outer proliferation center (OPC). This neuroepithelium is located at the surface of the developing optic lobe, where it generates the neurons of the medulla Proteasome-IN-1 and SEMA3F lamina neuropils. The OPC proliferates and expands during the first and second larval instars before a proneural wave sweeps across the epithelium, resulting in a switch to asymmetric division for generation of Proteasome-IN-1 neuroblasts (Doe, 2017; Holguera and Desplan, 2018). Immature cortex glia sit atop the OPC and send extrinsic cues to set the Proteasome-IN-1 balance between neuroepithelial expansion and neuroblast transition. Cortex glia activate Notch signaling in neuroepithelial cells through the membrane-bound ligand Serrate, which maintains epithelial cell proliferation and delays proneural wave progression (Prez-Gmez et al., 2013). Cortex glia also secrete the Epidermal Growth Factor (EGF) Spitz, which activates EGF Receptor (EGFR) signaling in the epithelium; EGFR activity inhibits Notch to promote proneural wave progression and the transition to neuroblasts (Morante et al., 2013). The relative strength of Notch and EGF signaling within the neuroepithelium governs Proteasome-IN-1 the timing of this transition (Egger et al., 2010; Yasugi et al., 2010). What controls the balance of these two glial-derived cues is not yet understood. More recently, expression of the chloride channel CIC-a in cortex glia was also shown to promote neuroepithelial expansion, suggesting that glia-mediated ion homeostasis within the niche can temporally control the transition to neurogenesis (Plazaola-Sasieta et al., 2019). Glia and the Timing of Neural Progenitor Proliferation In studies using primary murine neural progenitor cells were the first to demonstrate the ability of microglia to influence developmental neurogenesis. First, both embryonic and adult neural stem cells could migrate along gradients of microglia-conditioned medium (Aarum et al., 2003). Microglia were later found to secrete mitogenic factors that induce neural stem cell proliferation in a PI3K and Notch-dependent fashion (Morgan et al., 2004), similar to cortex glia (Prez-Gmez et al., 2013). Furthermore, addition of microglia can prolong neurogenesis in cultured subventricular zone-derived neurospheres (Walton et al., 2006). Finally, analysis of PU.1C/C mice, which disrupts microglial development, revealed a decrease in cortical progenitor proliferation (Antony et al., 2011). analysis of microglia-dependent embryonic neurogenesis is limited, yet microglia have been shown to regulate the timing of neural differentiation in the zebrafish developing retina (Huang et al., 2012). Here, knockdown of the cell surface protein Colony stimulating factor-1 receptor suppressed entry of microglia into the CNS. Lack of microglia delayed the differentiation of retinal neurons and increased the number of proliferative progenitors, resulting in an immature optic lobe (Huang et al., 2012). In mammals, both microglia and macroglia regulate adult neurogenesis (reviewed in Falk and G?tz, 2017). Co-culturing astrocytes with adult NSCs derived from the hippocampus is sufficient to induce NSC proliferation (Song et al., 2002). Elegant data both and have since defined that complex extrinsic cues from astrocytes and oligodendrocyte precursor cells can bias adult NSCs toward neurogenic or gliogenic trajectories (Peretto et al., 2004; Lie et al., 2005; Barkho et al., 2006; Ferrn et al., 2011; Ashton et al., 2012; Shin et al., 2015). For example, astrocyte-derived Wnt7a instructs neurogenesis (Moreno-Estells et al., 2012), whereas oligodendrocyte precursor-derived Wnt3a promotes generation of additional oligodendrocyte precursor cells (Ortega et al., 2013). Microglia are primarily thought to regulate hippocampal neurogenesis through pruning of supernumerary neurons that undergo apoptosis (discussed further below, Sierra et al., 2010). Interestingly, a recent report found that microglial phagocytosis induces a cell-autonomous transcriptional cascade, resulting in secretion of factors that are required for continued proliferation of residual.