Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

Abstract

The developing nervous system is a complex yet organized system of neurons, glial support cells, and extracellular matrix that arranges into an elegant, highly structured network. The extracellular and intracellular events that guide axons to their target locations have been well characterized in many regions of the developing nervous system. However, despite extensive work, we have a poor understanding of how axonal growth cones interact with surrounding glial cells to regulate network assembly. Gliato-growth cone communication is either direct through cellular contacts or indirect through modulation of the local microenvironment via the secretion of factors or signaling molecules. Microglia, oligodendrocytes, astrocytes, Schwann cells, neural progenitor cells, and olfactory ensheathing cells have all been demonstrated to directly impact axon growth and guidance. Expanding our understanding of how different glial cell types directly interact with growing axons throughout neurodevelopment will inform basic and clinical neuroscientists. For example, identifying the key cellular players beyond the axonal growth cone itself may provide translational clues to develop therapeutic interventions to modulate neuron growth during development or regeneration following injury. This review will provide an overview of the current knowledge about glial involvement in development of the nervous system, specifically focusing on how glia directly interact with growing and maturing axons to influence neuronal connectivity. This focus will be applied to the clinically-relevant field of regeneration following spinal cord injury, highlighting how a better understanding of the roles of glia in neurodevelopment can inform strategies to improve axon regeneration after injury.

Neural Cadherin Plays Distinct Roles for Neuronal Survival and Axon Growth under Different Regenerative Conditions

“…Numerous studies have demonstrated that environmental factors also contribute to axon regeneration. Among such factors, astrocytes have been studied extensively (Silver et al, 2014;Anderson et al, 2016); astrocytes are not only a source of growth factors but they also serve as physical scaffolds, and provide pathways for CNS axons to adhere and migrate (Tom et al, 2004;Rigby et al, 2020). For example, in the spinal cord of PTEN-deleted mice, regenerating axons almost always grow along the astrocytic processes that span the lesion site (i.e.…”

More Than Mortar: Glia as Architects of Nervous System Development and Disease

“…The spatial and temporal precision of neuronal positioning and neurite extension is essential for the assembly of correct neural circuits and for correct nervous system organization (Buchsbaum and Cappello, 2019). Glial cells also migrate to specific positions in the nervous system after being born (Klämbt, 2009), where they act as scaffolds for neuronal migration, and modify the environment to guide neuronal migration and subsequent neurite outgrowth (Allen and Lyons, 2018;Song and Dityatev, 2018;Rigby et al, 2020).…”

“…Glial cells within the PNS and CNS are essential for proper guidance of axon and dendrite outgrowth (Mason and Sretavan, 1997;Poeck et al, 2001;Hidalgo, 2003;Chotard and Salecker, 2004;Chotard et al, 2005;Learte and Hidalgo, 2007;Procko and Shaham, 2010;Avraham et al, 2020;Rigby et al, 2020). This is required for directing information flow in local circuits and is also essential for broad nervous system organization.…”

“…Glia are critical regulators of axon targeting during development (Mason and Sretavan, 1997;Hidalgo, 2003;Chotard and Salecker, 2004;Learte and Hidalgo, 2007;Procko and Shaham, 2010;Rigby et al, 2020) and during regeneration (Doherty et al, 2014;Lewis and Kucenas, 2014;Jessen and Mirsky, 2016;Purice et al, 2016;Sofroniew, 2018). Accordingly, changes to glial signaling can profoundly impact axon regrowth after injury.…”

“…Accordingly, changes to glial signaling can profoundly impact axon regrowth after injury. As this topic has been recently reviewed (Rigby et al, 2020); here, we will focus on how defective glial signaling during neuronal migration contributes to human disease. Neural migration disorders (NMDs) are characterized by defects in cortical neuron migration that produce a spectrum of phenotypes including intellectual disability, epilepsy, developmental delay, and motor impairment (Buchsbaum and Cappello, 2019).…”