Abstract
Glial cells form part of the neural stem cell niche and express a wide variety of ion channels; however, the contribution of these channels to nervous system development is poorly understood. We explored the function of the Drosophila ClC‐a chloride channel, since its mammalian ortholog CLCN2 is expressed in glial cells, and defective channel function results in leukodystrophies, which in humans are accompanied by cognitive impairment. We found that ClC‐a was expressed in the niche in cortex glia, which are closely associated with neurogenic tissues. Characterization of loss‐of‐function ClC‐a mutants revealed that these animals had smaller brains and widespread wiring defects. We showed that ClC‐a is required in cortex glia for neurogenesis in neuroepithelia and neuroblasts, and identified defects in a neuroblast lineage that generates guidepost glial cells essential for photoreceptor axon guidance. We propose that glia‐mediated ionic homeostasis could nonautonomously affect neurogenesis, and consequently, the correct assembly of neural circuits.
Highlights
The remarkable proliferative capacity of stem cells requires tight regulation to ensure generation of the appropriate amount of cells and tissue homeostasis during development
We propose that the expression of ion channels in the glial niche can shape the development of the nervous system, controlling the number of glia and neurons generated, as well as the connectivity of the latter
We found that superficial ClC-a+ nuclei on top of the OPC neuroepithelium corresponded to a subtype of cortex glia called surface-associated cortex glia (Morante et al, 2013), which lie beneath perineural and subperineural glia (Figure 1j). miRNA mir-8 (Karres, Hilgers, Carrera, Treisman, & Cohen, 2007), a marker for this subtype of cortex glia (Morante et al, 2013), colocalized with ClC-a protein in cells covering the OPC and the process separating the LPC from the lopn (Figure 1k)
Summary
The remarkable proliferative capacity of stem cells requires tight regulation to ensure generation of the appropriate amount of cells and tissue homeostasis during development. The finding that ClC-2 is expressed during development in glial precursors and is required for their differentiation (Hou et al, 2018), together with the fact that intellectual impairment can arise from connectivity defects, suggests that this channel may have additional functions during neural development To explore this possibility, we leveraged the functional parallelisms between vertebrate and Drosophila glia (Chotard & Salecker, 2004; Corty & Freeman, 2013; Freeman & Doherty, 2006) and used the fly, where neurogenesis has been extensively studied, the niche is simpler than in vertebrates, and the ClC-a gene codes for the fly homolog of the vertebrate ClC-2 chloride channel. One of the secondary consequences of reduced neurogenesis was the significantly limited production of guidepost glial cells, which gave rise to nonautonomous neural circuit assembly phenotypes in photoreceptors Both neurogenic and connectivity defects could be rescued by glial-specific expression of the rat ClC-2 vertebrate channel. We propose that the expression of ion channels in the glial niche can shape the development of the nervous system, controlling the number of glia and neurons generated, as well as the connectivity of the latter
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