Astrocytes are predominant glial cells that tile the central nervous system (CNS). A cardinal feature of astrocytes is their complex and visually enchanting morphology, referred to as bushy, spongy, and star-like. A central precept of this review is that such complex morphological shapes evolved to allow astrocytes to contact and signal with diverse cells at a range of distances in order to sample, regulate, and contribute to the extracellular milieu, and thus participate widely in cell-cell signaling during physiology and disease. The recent use of improved imaging methods and cell-specific molecular evaluations has revealed new information on the structural organization and molecular underpinnings of astrocyte morphology, the mechanisms of astrocyte morphogenesis, and the contributions to disease states of reduced morphology. These insights have reignited interest in astrocyte morphological complexity as a cornerstone of fundamental glial biology and as a critical substrate for multicellular spatial and physiological interactions in the CNS. 

Astrocyte morphology

Glial cells in the central nervous system (CNS) are composed of oligodendrocytes, astrocytes and microglia. They contribute more than half of the total cells of the CNS, and are essential for neural development and functioning. Studies on the fate specification, differentiation, and functional diversification of glial cells mainly rely on the proper use of cell- or stage-specific molecular markers. However, as cellular markers often exhibit different specificity and sensitivity, careful consideration must be given prior to their application to avoid possible confusion. Here, we provide an updated overview of a list of well-established immunological markers for the labeling of central glia, and discuss the cell-type specificity and stage dependency of their expression. 

/pdf/immunological-markers-for-central-nervous-system-glia-1zjxptb3.pdf

Immunological Markers for Central Nervous System Glia

Human cortical radial glial cells are primary neural stem cells that give rise to cortical glutaminergic projection pyramidal neurons, glial cells (oligodendrocytes and astrocytes) and olfactory bulb GABAergic interneurons. One of prominent features of the human cortex is enriched with glial cells, but there are major gaps in understanding how these glial cells are generated. Herein, by integrating analysis of published human cortical single-cell RNA-Seq datasets with our immunohistochemistical analyses, we show that around gestational week 18, EGFR-expressing human cortical truncated radial glial cells (tRGs) give rise to basal multipotent intermediate progenitors (bMIPCs) that express EGFR, ASCL1, OLIG2 and OLIG1. These bMIPCs undergo several rounds of mitosis and generate cortical oligodendrocytes, astrocytes and olfactory bulb interneurons. We also characterized molecular features of the cortical tRG. Integration of our findings suggests a general picture of the lineage progression of cortical radial glial cells, a fundamental process of the developing human cerebral cortex.

/pdf/developmental-origins-of-human-cortical-oligodendrocytes-and-34nar06u9w.pdf

Developmental Origins of Human Cortical Oligodendrocytes and Astrocytes.

During early telencephalic development, intricate processes of regional patterning and neural stem cell (NSC) fate specification take place. However, our understanding of these processes in primates, including both conserved and species-specific features, remains limited. Here, we profiled 761,529 single-cell transcriptomes from multiple regions of the prenatal macaque telencephalon. We deciphered the molecular programs of the early organizing centers and their cross-talk with NSCs, revealing primate-biased galanin-like peptide (GALP) signaling in the anteroventral telencephalon. Regional transcriptomic variations were observed along the frontotemporal axis during early stages of neocortical NSC progression and in neurons and astrocytes. Additionally, we found that genes associated with neuropsychiatric disorders and brain cancer risk might play critical roles in the early telencephalic organizers and during NSC progression. Description INTRODUCTION Telencephalic development involves intricate molecular processes that regulate the spatial identity of the neural cells over time. Early patterning centers specify neural stem cells (NSCs), which generate neurons and glia. We explored these events in macaque monkeys and human brain organoids, using single-cell transcriptomics. RATIONALE The molecular mechanisms pivotal to brain development have been characterized in rodents but remain elusive in primates, limiting our comprehension of the origins and dysfunctions of higher-level cognitive abilities. Moreover, in primates, including humans, a dearth of information remains on the early molecular events underlying the diversification of telencephalic regions and cortical areas, as NSCs traverse neuronal and glial trajectories. RESULTS We dissected multiple regions of rhesus macaque prenatal telencephalon and conducted single-cell RNA sequencing on over 761,000 cells, from the phase before neurogenesis through to mid-gliogenesis. We distinguished transcriptomically defined cell subtypes representing dorsal and ventral NSCs, excitatory and inhibitory neurons, glial cells, and non-neural cells and characterized their molecular dynamics across regions as they navigated lineage trajectories. We identified putative early progenitors of telencephalic organizing centers and predicted the gene regulatory networks that orchestrate their patterning function, including ZIC transcription factors (TFs) that target fibroblast growth factor (FGF) signaling–related genes in the anteroventral domain, and their signaling cross-talk with regional NSCs. Transcriptomic comparisons with mouse revealed primate-biased expression of galanin-like peptide (GALP) in the anteroventral organizer. Furthermore, we observed that GALP ligand enhanced cortical NSC proliferation in human and monkey brain organoids and in injected mouse embryos. Cortical NSCs displayed regional diversification in early subtypes and in outer radial glial (RG) cells. Moreover, we identified region-specific gene expression cascades throughout the NSC state transitions, including retinoic acid (RA) signaling components in the frontal region. Along the excitatory neuronal lineage, regional variance became pronounced late during maturation, when synaptic connections are established and laminar neuronal identities refined. However, putative cell-autonomous mechanisms may also contribute to neuron regional diversity. This was evident in vitro, where cortical NSC-derived excitatory neurons expressed region-specific genes, including the prefrontal-enriched RA signaling-associated CBLN2, even in the absence of outside synaptic inputs. By contrast, interneurons appeared more transcriptomically homogeneous across regions. Lastly, transcriptomic divergence in astrocytes emerged during late differentiation, wherein they displayed region-specific competence in responding to vascular signals, including Notch ligands. Whereas previous studies have reported neuropsychiatric disorder–associated genes that function in prenatal and/or adult neuronal and glial cells, we found risk genes that are expressed in the patterning centers and during the progression of dorsal and ventral NSCs. Thus, these disorders may have an even earlier developmental origin, implicating dysfunctional telencephalic patterning and altered spatiotemporal identity of the RG cells. CONCLUSION We have elucidated the molecular mechanisms underlying the progression of NSC identity and the regional specification of neurons and glia during macaque telencephalic development, highlighting early events as possible risk factors for brain disorders. This resource enables further exploration of primate and human brain development, evolution, and diseases. Regionalization of macaque telencephalon. Single-cell transcriptomics of prenatal macaque telencephalic regions distinguished subtypes spanning development. The transcriptome of putative organizers and their TF network were defined. Primate-expressed GALP modulates NSC proliferation in vitro and in vivo. Differentially expressed gene (DEG) analysis revealed regional divergence along NSC progression, neurogenesis, and gliogenesis. Expression of brain disease–associated genes in organizers denotes risk during early development.

Molecular programs of regional specification and neural stem cell fate progression in macaque telencephalon

Studies on the development of central nervous system (CNS) primarily rely on the use of specific molecular markers for different types of neural cells. S100B is widely being used as a specific marker for astrocytes in the CNS. However, the specificity of its expression in astrocyte lineage has not been systematically investigated and thus has remained a lingering issue. In this study, we provide several lines of molecular and genetic evidences that S100B is expressed in both protoplasmic astrocytes and myelinating oligodendrocytes. In the developing spinal cord, S100B is first expressed in the ventral neuroepithelial cells, and later in ALDH1L1+/GS+ astrocytes in the gray matter. Meanwhile, nearly all the S100B+ cells in the white matter are SOX10+/MYRF+ oligodendrocytes. Consistent with this observation, S100B expression is selectively lost in the white matter in Olig2-null mutants in which oligodendrocyte progenitor cells (OPCs) are not produced, and dramatically reduced in Myrf-conditional knockout mutants in which OPCs fail to differentiate. Similar expression patterns of S100B are observed in the developing forebrain. Based on these molecular and genetic studies, we conclude that S100B is not a specific marker for astrocyte lineage; instead, it marks protoplasmic astrocytes in the gray matter and differentiating oligodendrocytes.

/pdf/s100b-is-selectively-expressed-by-gray-matter-protoplasmic-2ib6vlnfrt.pdf

S100B is selectively expressed by gray matter protoplasmic astrocytes and myelinating oligodendrocytes in the developing CNS.

Mouse cortical radial glial cells (RGCs) are primary neural stem cells that give rise to cortical oligodendrocytes, astrocytes, and olfactory bulb (OB) GABAergic interneurons in late embryogenesis. There are fundamental gaps in understanding how these diverse cell subtypes are generated. Here, by combining single-cell RNA-Seq with intersectional lineage analyses, we show that beginning at around E16.5, neocortical RGCs start to generate ASCL1+EGFR+ apical multipotent intermediate progenitors (MIPCs), which then differentiate into basal MIPCs that express ASCL1, EGFR, OLIG2, and MKI67. These basal MIPCs undergo several rounds of divisions to generate most of the cortical oligodendrocytes and astrocytes and a subpopulation of OB interneurons. Finally, single-cell ATAC-Seq supported our model for the genetic logic underlying the specification and differentiation of cortical glial cells and OB interneurons. Taken together, this work reveals the process of cortical radial glial cell lineage progression and the developmental origins of cortical astrocytes and oligodendrocytes.

/pdf/decoding-cortical-glial-cell-development-1oq2afa01b.pdf

Decoding Cortical Glial Cell Development

Specification of the progenitors' regional identity is a pivotal step during development of the cerebral cortex and basal ganglia. The molecular mechanisms underlying progenitor regionalization, however, are poorly understood. Here we showed that the transcription factor Vax1 was highly expressed in the developing subpallium. In its absence, the RNA-Seq analysis, in situ RNA hybridization, and immunofluorescence staining results showed that the cell proliferation was increased in the subpallium, but the neuronal differentiation was blocked. Moreover, the dLGE expands ventrally, and the vLGE, MGE, and septum get smaller. Finally, overexpressed VAX1 in the LGE progenitors strongly inhibits Gsx2 expression. Taken together, our findings show that Vax1 is crucial for subpallium regionalization by repressing Gsx2.

/pdf/transcription-factor-vax1-regulates-the-regional-10oc6ui0mw.pdf

Transcription Factor VAX1 Regulates the Regional Specification of the Subpallium Through Repressing Gsx2

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Decoding Cortical Glial Cell Development

Transcription Factor VAX1 Regulates the Regional Specification of the Subpallium Through Repressing Gsx2