A full list of affiliations appears at the end of the paper. 'N euroglia' or 'glia' are collective terms describing cells of neuroepithelial (oligodendrocytes, astrocytes, oligodendrocyte progenitor cells, ependymal cells), neural crest (peripheral glia), and myeloid (microglia) origin. Changes in neuroglia associated with diseases of the CNS have been noted, characterized, and conceptualized from the very dawn of neuroglial research. Rudolf Virchow, in a lecture to students and medical doctors in 1858, stressed that 'this very interstitial tissue [that is, neuroglia] of the brain and spinal marrow is one of the most frequent seats of morbid change... ' 1. Changes in the shape, size, or number of glial cells in various pathological contexts have been frequently described by prominent neuroanatomists 2. In particular, hypertrophy of astrocytes was recognized very early as an almost universal sign of CNS pathology: 'the protoplasmic glia elements [that is, astrocytes] are really the elements which exhibit a morbid hypertrophy in pathological conditions' 3. Neuroglial proliferation was thought to accompany CNS lesions, leading to early suggestions that proliferating glia fully replaced damaged neuronal elements 4. Thus, a historical consensus was formed that a change in 'the appearance of neuroglia serves as a delicate indicator of the action of noxious influences upon the central nervous system, ' and the concept of 'reactionary change or gliosis' was accepted 5. While the origin of 'gliosis' is unclear (glia + osis in Greek means 'glial condition or process'; in Latin the suffix-osis acquired the additional meaning of 'disease'; hence 'astrogliosis'

Astrocytes are no longer seen as a homogenous population of cells. In fact, recent studies indicate that astrocytes are morphologically and functionally diverse and play critical roles in neurodevelopmental diseases such as Rett syndrome and fragile X mental retardation. This review summarizes recent advances in astrocyte development, including the role of neural tube patterning in specification and developmental functions of astrocytes during synaptogenesis. We propose here that a precise understanding of astrocyte development is critical to defining heterogeneity and could lead advances in understanding and treating a variety of neuropsychiatric diseases.

The mechanisms controlling the transition from neurogenesis to gliogenesis in the vertebrate CNS are incompletely understood. We identified a family of transcription factors, called NFI genes, which are induced throughout the spinal cord ventricular zone (VZ) concomitantly with the induction of GLAST, an early marker of gliogenesis. NFIA is both necessary and sufficient for GLAST induction in the VZ. Unexpectedly, NFIA is also essential for the continued inhibition of neurogenesis in VZ progenitors. This function is mediated by the requirement of NFIA for the expression of HES5, a Notch effector. However, Notch effectors are unable to promote glial-fate specification in the absence of NFIA. Thus, NFIA links the abrogation of neurogenesis to a generic program of gliogenesis, in both astrocyte and oligodendrocyte VZ progenitors. At later stages, NFIA promotes migration and differentiation of astrocyte precursors, a function that is antagonized in oligodendrocyte precursors by Olig2.

SUMMARY Transcriptional cascades that operate over the course of lineage development are fundamental mechanisms that control cellular differentiation. In the developing central nervous system (CNS), these mechanisms are well characterized during neurogenesis, but remain poorly defined during neural stem cell commitment to the glial lineage. NFIA is a transcription factor that plays a crucial role in the onset of gliogenesis; we found that its induction is regulated by the transcription factor Sox9 and that this relationship mediates the initiation of gliogenesis. Subsequently, Sox9 and NFIA form a complex and coregulate a set of genes induced after glial initiation. Functional studies revealed that a subset of these genes, Apcdd1 and Mmd2, perform key migratory and metabolic roles during astro-gliogenesis, respectively. In sum, these studies delineate a transcriptional regulatory cascade that operates during the initiation of gliogenesis and identifies a unique set of genes that regulate key aspects of astro-glial precursor physiology during development.

Astrocytes are the most abundant cell type in the brain, where they perform a wide array of functions, yet the nature of their cellular heterogeneity and how it oversees these diverse roles remains shrouded in mystery. Using an intersectional fluorescence-activated cell sorting–based strategy, we identified five distinct astrocyte subpopulations present across three brain regions that show extensive molecular diversity. Application of this molecular insight toward function revealed that these populations differentially support synaptogenesis between neurons. We identified correlative populations in mouse and human glioma and found that the emergence of specific subpopulations during tumor progression corresponded with the onset of seizures and tumor invasion. In sum, we have identified subpopulations of astrocytes in the adult brain and their correlates in glioma that are endowed with diverse cellular, molecular and functional properties. These populations selectively contribute to synaptogenesis and tumor pathophysiology, providing a blueprint for understanding diverse astrocyte contributions to neurological disease.

During midgestation, mammalian neural precursor cells (NPCs) differentiate only into neurons. Generation of astrocytes is prevented at this stage, because astrocyte-specific gene promoters are methylated. How the subsequent switch from suppression to expression of astrocytic genes occurs is unknown. We show in this study that Notch ligands are expressed on committed neuronal precursors and young neurons in mid-gestational telencephalon, and that neighboring Notch-activated NPCs acquire the potential to become astrocytes. Activation of the Notch signaling pathway in midgestational NPCs induces expression of the transcription factor nuclear factor I, which binds to astrocytic gene promoters, resulting in demethylation of astrocyte-specific genes. These findings provide a mechanistic explanation for why neurons come first: committed neuronal precursors and young neurons potentiate remaining NPCs to differentiate into the next cell lineage, astrocytes.

Astrocytes are morphologically complex, ubiquitous cells that are viewed as a homogeneous population tiling the entire central nervous system (CNS). However, this view has been challenged in the last few years with the availability of RNA sequencing, immunohistochemistry, electron microscopy, morphological reconstruction, and imaging data. These studies suggest that astrocytes represent a diverse population of cells and that they display brain area– and disease–specific properties and functions. In this review, we summarize these observations, emphasize areas where clear conclusions can be made, and discuss potential unifying themes. We also identify knowledge gaps that need to be addressed in order to exploit astrocyte diversity as a biological phenomenon of physiological relevance in the CNS. We thus provide a summary and a perspective on astrocyte diversity in the vertebrate CNS.

Astrocytes constitute the most abundant cell type in the central nervous system (CNS) and play diverse functional roles, but the ontogenetic origins of this phenotypic diversity are poorly understood. We have investigated whether positional identity, a fundamental organizing principle governing the generation of neuronal subtype diversity, is also relevant to astrocyte diversification. We identified three positionally distinct subtypes of white-matter astrocytes (WMA) in the spinal cord, which can be distinguished by the combinatorial expression of Reelin and Slit1. These astrocyte subtypes derive from progenitor domains expressing the homeodomain transcription factors Pax6 and Nkx6.1, respectively. Loss- and gain-of-function experiments indicate that the positional identity of these astrocyte subtypes is controlled by Pax6 and Nkx6.1 in a combinatorial manner. Thus, positional identity is an organizing principle underlying astrocyte, as well as neuronal, subtype diversification and is controlled by a homeodomain transcriptional code whose elements are reutilized following the specification of neuronal identity earlier in development.