Glial cells more than support cells?

Glial cells are the most abundant cells in the human brain and have long been considered as passive supporting cells for neurons. In contrast to the extensive studies on various neuronal functions in the nervous system, we still have limited knowledge about glial cells. Recently a number of pioneering studies have provided convincing evidence that glia play active roles in development and function of the central nervous system. This review discusses recent advances in our understanding of the molecular mechanisms underlying glial cell differentiation. We then highlight some of the novel findings about glial function, i.e. the role of glia in synaptogenesis and the intricate relationship between astrocytes and adult neural stem cells. Finally, we summarize the emerging studies that implicate abnormalities in the formation or maintenance of glia leading to severe brain diseases, such as Alexander disease, glioblastoma and multiple sclerosis, and potential therapeutic strategies to tackle these diseases.     

Glial influences on neural stem cell development: cellular niches for adult neurogenesis

Neural stem cells continually generate new neurons in very limited regions of the adult mammalian central nervous system. In the neurogenic regions there are unique and highly specialized microenvironments (niches) that tightly regulate the neuronal development of adult neural stem cells. Emerging evidence suggests that glia, particularly astrocytes, have key roles in controlling multiple steps of adult neurogenesis within the niches, from proliferation and fate specification of neural progenitors to migration and integration of the neuronal progeny into pre-existing neuronal circuits in the adult brain. Identification of specific niche signals that regulate these sequential steps during adult neurogenesis might lead to strategies to induce functional neurogenesis in other brain regions after injury or degenerative neurological diseases.     

A unified hypothesis on the lineage of neural stem cells

For many years, it was assumed that neurons and glia in the central nervous system were produced from two distinct precursor pools that diverged early during embryonic development. This theory was partially based on the idea that neurogenesis and gliogenesis occurred during different periods of development, and that neurogenesis ceased perinatally. However, there is now abundant evidence that neural stem cells persist in the adult brain and support ongoing neurogenesis in restricted regions of the central nervous system. Surprisingly, these stem cells have the characteristics of fully differentiated glia. Neuroepithelial stem cells in the embryonic neural tube do not show glial characteristics, raising questions about the putative lineage from embryonic to adult stem cells. In the developing brain, radial glia have long been known to produce cortical astrocytes, but recent data indicate that radial glia might also divide asymmetrically to produce cortical neurons. Here we review these new developments and propose that the stem cells in the central nervous system are contained within the neuroepithelial --> radial glia --> astrocyte lineage.     

miR-31 mutants reveal continuous glial homeostasis in the adult Drosophila brain

The study of adult neural cell production has concentrated on neurogenesis. The mechanisms controlling adult gliogenesis are still poorly understood. Here, we provide evidence for a homeostatic process that maintains the population of glial cells in the Drosophila adult brain. Flies lacking microRNA miR-31a start adult life with a normal complement of glia, but transiently lose glia due to apoptosis. miR-31a expression identifies a subset of predominantly gliogenic adult neural progenitor cells. Failure to limit expression of the predicted E3 ubiquitin ligase, Rchy1, in these cells results in glial loss. After an initial decline in young adults, glial numbers recovered due to compensatory overproduction of new glia by adult progenitor cells, indicating an unexpected plasticity of the Drosophila nervous system. Experimentally induced ablation of glia was also followed by recovery of glia over time. These studies provide evidence for a homeostatic mechanism that maintains the number of glia in the adult fly brain.     

Glia-neuron interactions in the nervous system of Caenorhabditis elegans

A century and a half after first being described, glia are beginning to reveal their intricate and important roles in nervous system development and function. Recent studies in the nematode Caenorhabditis elegans suggest that this invertebrate will provide important insight into these roles. Studies of C. elegans have revealed a connection between glial ensheathment of neurons and tubulogenesis, have uncovered glial roles in neurite growth, navigation, and function, and have demonstrated roles for glia and glia-like cells in synapse formation and function. Given the conservation of basic anatomical, functional and molecular features of the nervous systems between C. elegans and vertebrates, these recent advances are likely to be informative in describing nervous system assembly and function in all organisms possessing a nervous system.     

VEGF in the nervous system

Vascular endothelial growth factor (VEGF, VEGFA) is critical for blood vessel growth in the developing and adult nervous system of vertebrates. Several recent studies demonstrate that VEGF also promotes neurogenesis, neuronal patterning, neuroprotection and glial growth. For example, VEGF treatment of cultured neurons enhances survival and neurite growth independently of blood vessels. Moreover, evidence is emerging that VEGF guides neuronal migration in the embryonic brain and supports axonal and arterial co-patterning in the developing skin. Even though further work is needed to understand the various roles of VEGF in the nervous system and to distinguish direct neuronal effects from indirect, vessel-mediated effects, VEGF can be considered a promising tool to promote neuronal health and nerve repair.Key words: VEGF, neuron, neurogenesis, glia, endothelial cell, blood vessel, angiogenic niche     

Ancestral roles of glia suggested by the nervous system of Caenorhabditis elegans

The nematode Caenorhabditis elegans has a simple nervous system with glia restricted primarily to sensory organs. Some of the activities that would be provided by glia in the mammalian nervous system are either absent or provided by non-glial cell types in C. elegans, with only a select set of mammalian glial activities being similarly provided by specialized glial cells in this animal. These observations suggest that ancestral roles of glia may be to modulate neuronal morphology and neuronal sensitivity in sensory organs.     

Maintenance of Glia in the Optic Lamina Is Mediated by EGFR Signaling by Photoreceptors in Adult Drosophila

The late onset of neurodegeneration in humans indicates that the survival and function of cells in the nervous system must be maintained throughout adulthood. In the optic lamina of the adult Drosophila, the photoreceptor axons are surrounded by multiple types of glia. We demonstrated that the adult photoreceptors actively contribute to glia maintenance in their target field within the optic lamina. This effect is dependent on the epidermal growth factor receptor (EGFR) ligands produced by the R1-6 photoreceptors and transported to the optic lamina to act on EGFR in the lamina glia. EGFR signaling is necessary and sufficient to act in a cell-autonomous manner in the lamina glia. Our results suggest that EGFR signaling is required for the trafficking of the autophagosome/endosome to the lysosome. The loss of EGFR signaling results in cell degeneration most likely because of the accumulation of autophagosomes. Our findings provide in vivo evidence for the role of adult neurons in the maintenance of glia and a novel role for EGFR signaling in the autophagic flux.     

Extracellular matrix: functions in the nervous system

An astonishing number of extracellular matrix glycoproteins are expressed in dynamic patterns in the developing and adult nervous system. Neural stem cells, neurons, and glia express receptors that mediate interactions with specific extracellular matrix molecules. Functional studies in vitro and genetic studies in mice have provided evidence that the extracellular matrix affects virtually all aspects of nervous system development and function. Here we will summarize recent findings that have shed light on the specific functions of defined extracellular matrix molecules on such diverse processes as neural stem cell differentiation, neuronal migration, the formation of axonal tracts, and the maturation and function of synapses in the peripheral and central nervous system.     

Glial cells in synaptic plasticity.

Plasticity of synaptic transmission is believed to be the cellular basis for learning and memory, and depends upon different pre- and post-synaptic neuronal mechanisms. Recently, however, an increasing number of studies have implicated a third element in plasticity; the perisynaptic glial cell. Originally glial cells were thought to be important for metabolic maintenance and support of the nervous system. However, work in the past decade has clearly demonstrated active involvement of glia in stability and overall nervous system function as well as synaptic plasticity. Through specific modulation of glial cell function, a wide variety of roles for glia in synaptic plasticity have been uncovered. Furthermore, interesting circumstantial evidence suggests a glial involvement in multiple other types of plasticity. We will discuss recent advances in neuron-glial interactions that take place during synaptic plasticity and explore different plasticity phenomena in which glial cells may be involved.     

Glial cells

The nervous system is built from two broad categories of cells, neurones and glial cells. The glial cells outnumber the neurones and the two cell types occupy a comparable amount of space in nervous tissue. The main glial cell types are, in the central nervous system, astrocytes and oligodendrocytes and, in the peripheral nervous system, Schwann cells, enteric glial cells and satellite cells. In the embryo, glial cells form a cellular framework that permits the development of the rest of the nervous system, and regulate neuronal survival and differentiation. The best known function of glia in the adult is the formation of myelin sheaths around axons thus allowing the fast conduction of signalling essential for nervous system function. Glia also maintain appropriate concentrations of ions and neurotransmitters in the neuronal environment. Increasing body of evidence indicates that glial cells are essential regulators of the formation, maintenance and function of synapses, the key functional unit of the nervous system.     

Meteorin: a secreted protein that regulates glial cell differentiation and promotes axonal extension

Glial cells are major components of the nervous system. The roles of these cells are not fully understood, however. We have now identified a secreted protein, designated Meteorin, that is expressed in undifferentiated neural progenitors and in the astrocyte lineage, including radial glia. Meteorin selectively promoted astrocyte formation from mouse cerebrocortical neurospheres in differentiation culture, whereas it induced cerebellar astrocytes to become radial glia. Meteorin also induced axonal extension in small and intermediate neurons of sensory ganglia by activating nearby satellite glia. These observations suggest that Meteorin plays important roles in both glial cell differentiation and axonal network formation during neurogenesis.     

Sculpting the nervous system: glial control of neuronal development

Glial cells are not passive spectators during nervous system assembly, rather they are active participants that exert significant control over neuronal development. Well-established roles for glia in shaping the developing nervous system include providing trophic support to neurons, modulating axon pathfinding, and driving nerve fasciculation. Exciting recent studies have revealed additional ways in which glial cells also modulate neurodevelopment. Glial cells regulate the number of neurons at early developmental stages by dynamically influencing neural precursor divisions, and at later stages by promoting neuronal cell death through engulfment. Glia also participate in the fine sculpting of neuronal connections by pruning excess axonal projections, shaping dendritic spines, and secreting multiple factors that promote synapse formation and functional maturation. These recent insights provide further compelling evidence that glial cells, through their diverse cellular actions, are essential contributors to the construction of a functionally mature nervous system.     

Targeted ablation of oligodendrocytes triggers axonal damage

Glial dysfunction has been implicated in a number of neurodegenerative diseases. In this study we investigated the consequences of glial and oligodendrocyte ablation on neuronal integrity and survival in Drosophila and adult mice, respectively. Targeted genetic ablation of glia was achieved in the adult Drosophila nervous system using the GAL80-GAL4 system. In mice, oligodendrocytes were depleted by the injection of diphtheria toxin in MOGi-Cre/iDTR double transgenic animals. Acute depletion of oligodendrocytes induced axonal injury, but did not cause neuronal cell death in mice. Ablation of glia in adult flies triggered neuronal apoptosis and resulted in a marked reduction in motor performance and lifespan. Our study shows that the targeted depletion of glia triggers secondary neurotoxicity and underscores the central contribution of glia to neuronal homeostasis. The models used in this study provide valuable systems for the investigation of therapeutic strategies to prevent axonal or neuronal damage.     

The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum

Copper is essential for brain metabolism, serving as a cofactor to superoxide dismutase, dopamine-beta-hydroxylase, amyloid precursor protein, ceruloplasmin, and other proteins required for normal brain function. The copper-transporting ATPases ATP7A and ATP7B play a central role in distribution of copper in the central nervous system; genetic mutations in ATP7A and ATP7B lead to severe neurodegenerative disorders, Menkes disease and Wilson disease, respectively. Although both ATP7A and ATP7B are required, their specific roles and regulation in the brain remain poorly understood. Using high-resolution imaging and functional assays, we demonstrate that ATP7A and ATP7B show cell-specific distribution in adult cerebellum, have distinct enzymatic characteristics, and are regulated differently during development. ATP7B is continuously expressed in Purkinje neurons (PN) where it delivers copper to the ferroxidase ceruloplasmin. ATP7A is a faster copper transporter than Wilson disease protein as evidenced by faster rates of catalytic reactions. The expression of ATP7A switches during development from PN to Bergmann glia, the cells supporting PN function in adult brain. Inactivation of ATP7B (Wilson disease protein) by gene knock-out induces a striking shift in the expression of the ATP7B target protein, ceruloplasmin, from PN to Bergmann glia, where ATP7A (Menkes disease protein) is present. The induced cell-specific change in expression restores copper delivery to ceruloplasmin via ATP7A. Overall, the results provide evidence for distinct functions of ATP7A and ATP7B in the cerebellum and illustrate a tight link between copper homeostasis in PN and Bergmann glia.     

Signaling in glial development: differentiation migration and axon guidance.

Glial cells have diverse functions that are necessary for the proper development and function of complex nervous systems. During development, a variety of reciprocal signaling interactions between glia and neurons dictate all parts of nervous system development. Glia may provide attractive, repulsive, or contact-mediated cues to steer neuronal growth cones and ensure that neurons find their appropriate synaptic targets. In fact, both neurons and glia may act as migrational substrates for one another at different times during development. Also, the exchange of trophic signals between glia and neurons is essential for the proper bundling, fasciculation, and ensheathement of axons as well as the differentiation and survival of both cell types. The growing number of links between glial malfunction and human disease has generated great interest in glial biology. Because of its relative simplicity and the many molecular genetic tools available, Drosophila is an excellent model organism for studying glial development. This review will outline the roles of glia and their interactions with neurons in the embryonic nervous system of the fly.     

CNS midline cells influence the division and survival of lateral glia in the Drosophila nervous system

Central nervous system (CNS) midline cells are essential for identity determination and differentiation of neurons in the Drosophila nervous system. It is not clear, however, whether CNS midline cells are also involved in the development of lateral glial cells. The roles of CNS midline cells in lateral glia development were elucidated using general markers for lateral glia, such as glial cell missing and reverse polarity, and specific enhancer trap lines labeling the longitudinal, A, B, medial cell body, peripheral, and exit glia. We found that CNS midline cells were necessary for the proper expression of glial cell missing, reverse polarity, and other lateral glia markers only during the later stages of development, suggesting that they are not required for initial identity determination. Instead, CNS midline cells appear to be necessary for proper division and survival of lateral glia. CNS midline cells were also required for proper positioning of three exit glia at the junction of segmental and intersegmental nerves, as well as some peripheral glia along motor and sensory axon pathways. This study demonstrated that CNS midline cells are extrinsically required for the proper division, migration, and survival of various classes of lateral glia from the ventral neuroectoderm.     

Evolutionarily conserved concepts in glial cell biology

The evolutionary conservation of glial cells has been appreciated since Ramon y Cajal and Del Rio Hortega first described the morphological features of cells in the nervous system. We now appreciate that glial cells have essential roles throughout life in most nervous systems. The field of glial cell biology has grown exponentially in the last ten years. This new wealth of knowledge has been aided by seminal findings in non-mammalian model systems. Ultimately, such concepts help us to understand glia in mammalian nervous systems. Rather than summarizing the field of glial biology, I will first briefly introduce glia in non-mammalian models systems. Then, highlight seminal findings across the glial field that utilized non-mammalian model systems to advance our understanding of the mammalian nervous system. Finally, I will call attention to some recent findings that introduce new questions about glial cell biology that will be investigated for years to come.