Evolving concepts of gliogenesis: a look way back and ahead to the next 25 years

Abstract

Glial cells are present in all organisms with a CNS and, with increasing brain complexity, glial cells have undergone substantive increases in cell number, diversity, and functions. Invertebrates, such as Drosophila, possess glial subtypes with similarity to mammalian astrocytes in their basic morphology and function, representing fertile ground for unraveling fundamental aspects of glial biology. Although glial subtypes in simple organisms may be relatively homogenous, emerging evidence suggests the possibility that mammalian astrocytes might be highly diversified to match the needs of local neuronal subtypes. In this Perspective, we review classic and new roles identified for astrocytes and oligodendrocytes by recent studies. We propose that delineating genetic and developmental programs across species will be essential to understand the core functions of glia that allow enhanced neuronal function and to achieve new insights into glial roles in higher-order brain function and neurological disease.

Figure 1. Complex Glia in Even Simple Organisms

Glial cells in C. elegans and Drosophila. All C. elegans glia are associated with sensory structures, though the CEPsh glia also infiltrate the worm CNS. Drosophila have similar SOP-derived glial subtypes in the periphery (data not shown) and more elaborate and functionally distinct subclasses of glia in the CNS. A list of well-defined glial molecular or morphological phenotypes and functions that are conserved in worms and flies (indicated for each animal by gray bars to left) are listed. See text for details.

Figure 2. The Burgess Shale in the Canadian Rockies Provides a Rich Fossil Record of Paleozoic Invertebrates

Figure 3. Evolutionary Glial Epochs: Increasing Complexity of the CNS Demanded New Glial Solutions and Diversity

Cnidarians lack a nervous system and glia. The first vertebrates of the Paleozoic era (5–600 million years ago) most likely contained glial cells. Fruit flies contain 10⁵ neurons and astroglia-like cells with many features in common with those of vertebrates, including responsiveness to injury. Invertebrates also contain nonmyelinating glia that ensheath long axons in the PNS, which may be related to oligodendrocytes and Schwann cells. In the Mesozoic era, jawless vertebrate fishes (agnatha) displayed neuronal diversity typical of vertebrates but lacked myelinated axon tracts. In contrast, jawed fishes possess myelinating oligodendrocytes of the CNS and Schwann cells of the peripheral nervous system. It is important to note that while zebrafish contain radial glial cells, definitive astrocytes have not yet been identified. Vertebrate astrocytes and reactive astrocytes are clearly present in mammals, such as the mouse, in which genetic tools allow dissection of potential astrocyte subtype heterogeneity. The human brain contains approximately 85 × 10⁶ million neurons and as much as 90% of the human brain is glial cells. Human astrocytes possess more elaborate morphology than that of rodents.

Figure 4. Speculative Concept of Astrocyte Scaffold and Functional “Astromeres”

Embryonic patterning is known to generate diversified radial glial cells in response to complex positional cues in the dorsal-ventral and anterior-posterior axis. This in turn results in production of neuronal and glial subtypes (oligodendrocytes, astrocytes). The limited migration of astrocytes suggests the possibility that positional information might be retained in cells as they mature. If so, a variety of organizational roles and local functions to optimally support neuronal subtypes might be encoded in regionally distinct astrocyte domains called “astromeres.”