Explore the vast range of titles available.

Key Points Astrocytes display numerous inter- and intra-regional distinctions, ranging from differences in their morphology to differential dynamics of calcium signalling. Astrocytes in specific neural circuits modulate neuronal activity, which affects a range of brain functions. Regionally encoded astrocyte functions are required for neuronal homeostasis and survival. Astrocyte heterogeneity is determined by the developmental patterning of the CNS and is refined in adulthood to produce highly specialized neuron–glia units. Under pathological conditions, reactive astrocytes display several molecular and functional changes that have a differential influence on disease outcome. New techniques will help to uncover the molecular and functional heterogeneity of astrocytes both in health and disease. Emerging evidence suggests that astrocytes may be as diverse in their physiological and functional characteristics as neurons. Ben Haim and Rowitch describe astrocyte heterogeneity, consider the mechanisms by which such diversity may arise and discuss the consequences of its disruption in disease. Although it is well established that all brain regions contain various neuronal subtypes with different functions, astrocytes have traditionally been thought to be homogenous. However, recent evidence has shown that astrocytes in the mammalian CNS display distinct inter- and intra-regional features, as well as functional diversity. In the CNS, astrocyte processes fill the local environment in non-overlapping domains. Therefore, a potential advantage of region-specified astrocytes might be their capacity to regulate local development or optimize local neural circuit function. An overview of the regional heterogeneity of neuron–astrocyte interactions indicates novel ways in which they could regulate normal neurological function and shows how they might become dysregulated in disease.

Although the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells show distinct layering. In the present study, we developed a high-content pipeline, the large-area spatial transcriptomic (LaST) map, which can quantify single-cell gene expression in situ. Screening 46 candidate genes for astrocyte diversity across the mouse cortex, we identified superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from those of neurons. Astrocyte layer features, established in the early postnatal cortex, mostly persisted in adult mouse and human cortex. Single-cell RNA sequencing and spatial reconstruction analysis further confirmed the presence of astrocyte layers in the adult cortex. Satb2 and Reeler mutations that shifted neuronal post-mitotic development were sufficient to alter glial layering, indicating an instructive role for neuronal cues. Finally, astrocyte layer patterns diverged between mouse cortical regions. These findings indicate that excitatory neurons and astrocytes are organized into distinct lineage-associated laminae.A new spatial transcriptomic approach reveals astrocyte heterogeneity across layers of the mammalian cerebral cortex. Astrocytes diversify into superficial-, mid- and deep-layer subtypes distinct from neuronal laminae, yet instructed by neuronal cues.

Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.

Oligodendrocytes and astrocytes are macroglial cells of the vertebrate central nervous system. These cells have diverse roles in the maintenance of neurological function. In the embryo, the genetic mechanisms that underlie the specification of macroglial precursors in vivo appear strikingly similar to those that regulate the development of the diverse neuron types. The switch from producing neuronal to glial subtype-specific precursors can be modelled as an interplay between region-restricted components and temporal regulators that determine neurogenic or gliogenic phases of development, contributing to glial diversity. Gaining insight into the developmental genetics of macroglia has great potential to improve our understanding of a variety of neurological disorders in humans.

Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing–remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2 -expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions. Single-cell RNA sequencing was used to construct a map of gene expression in lesions from brains of patients with multiple sclerosis, revealing distinct lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation.

During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblast–decidual interactions underlie common diseases of pregnancy, including pre-eclampsia and stillbirth. Here we profile the transcriptomes of about 70,000 single cells from first-trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals subsets of perivascular and stromal cells that are located in distinct decidual layers. There are three major subsets of decidual natural killer cells that have distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand–receptor complexes and a statistical tool to predict the cell-type specificity of cell–cell communication via these molecular interactions. Our data identify many regulatory interactions that prevent harmful innate or adaptive immune responses in this environment. Our single-cell atlas of the maternal–fetal interface reveals the cellular organization of the decidua and placenta, and the interactions that are critical for placentation and reproductive success. Transcriptomes of about 70,000 single cells from first-trimester deciduas and placentas reveal subsets of perivascular, stromal and natural killer cells in the decidua, with distinct immunomodulatory profiles that regulate the environment necessary for successful placentation.

Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases. A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes. The production and roles of reactive astrocytes Different types of reactive astrocyte are generated after various injuries and insults to the brain, but less is known about what these astrocyte subtypes do. Here, Shane Liddelow et al . describe how these reactive astrocytes are induced by neuroinflammatory microglia. The authors also explore the functional roles of reactive astrocytes in the progression of disease or damaged states, and show that A1 astrocytes contribute to the death of neurons in the central nervous system under certain conditions.

Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The ability of these tumours to resist almost all conventional and novel treatments relates, in part, to the unique cell-intrinsic and microenvironmental properties of neural tissues. In an attempt to encourage progress in our understanding and ability to successfully treat patients with brain tumours, Cancer Research UK convened an international panel of clinicians and laboratory-based scientists to identify challenges that must be overcome if we are to cure all patients with a brain tumour. The seven key challenges summarized in this Position Paper are intended to serve as foci for future research and investment.Brain cancer encompasses a diverse range of complex malignancies, many of which are associated with a poor prognosis and require more effective treatments. In this Position Paper, an international panel of clinicians and laboratory-based scientists convened by Cancer Research UK identify and discuss seven challenges that must be overcome if we are to cure all patients with a brain tumour.

Ageing causes a decline in tissue regeneration owing to a loss of function of adult stem cell and progenitor cell populations 1 . One example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs) 2 . A relatively overlooked potential source of this loss of function is the stem cell ‘niche’—a set of cell-extrinsic cues that include chemical and mechanical signals 3 , 4 . Here we show that the OPC microenvironment stiffens with age, and that this mechanical change is sufficient to cause age-related loss of function of OPCs. Using biological and synthetic scaffolds to mimic the stiffness of young brains, we find that isolated aged OPCs cultured on these scaffolds are molecularly and functionally rejuvenated. When we disrupt mechanical signalling, the proliferation and differentiation rates of OPCs are increased. We identify the mechanoresponsive ion channel PIEZO1 as a key mediator of OPC mechanical signalling. Inhibiting PIEZO1 overrides mechanical signals in vivo and allows OPCs to maintain activity in the ageing CNS. We also show that PIEZO1 is important in regulating cell number during CNS development. Thus we show that tissue stiffness is a crucial regulator of ageing in OPCs, and provide insights into how the function of adult stem and progenitor cells changes with age. Our findings could be important not only for the development of regenerative therapies, but also for understanding the ageing process itself. Aged progenitor cells in the rat central nervous system can be made to behave as young cells by reducing the stiffness of the tissue microenvironment, or by inhibiting the mechanosensitive protein PIEZO1.

Key Points Glia comprise 10–20% of cells in the Drosophila nervous system, and more than 90% of cells in the human brain. This implies that glial function is crucial for the increased complexity of neurological function that has emerged during evolution. The principal macroglial subtypes — astrocytes and oligodendrocytes — are derived from the neuroepithelium. Early studies led to the proposal that development of neurons preceded that of glial subtypes in vivo , and that oligodendrocytes in particular developed mostly at postnatal stages. However, it is now clear that the initial specification of spinal cord oligodendrocytes takes place in the embryo. Indications that neurons and glia might be specified by common mechanisms stemmed from the observation that oligodendrocyte precursor cells (OLPs) emerge from a discrete region in the ventral neural tube, rather than from diffuse locations. Marker analysis indicated that OLP development is initiated in the pMN domain of the spinal cord, which also gives rise to motor neurons. A prolonged period of sonic hedgehog (Shh) activity is necessary to ensure normal cell fate acquisition in pMN-oligodendrocyte progenitors, but later stages of OLP maturation are Shh-independent. The Olig1 and Olig2 genes, which probably act downstream of Shh, are required for establishment of the pMN domain. Olig proteins seem to promote oligodendrocyte cell fate while inhibiting astrocyte development. Studies of Olig1 and Olig2 mutants have demonstrated that OLPs and most astrocyte precursors are established in mutually exclusive domains by molecularly independent mechanisms. In the embryonic brain, OLPs develop primarily from ventral regions of the telencephalon. Astrocytes in the brain derive initially from the neuroepithelium through a radial glial intermediate, whereas at later stages they derive from the dorsolateral subventricular zone. The switch from neuronal to glial production in the pMN domain seems to require the Delta–Notch pathway and the transcription factor Sox9, coupled with downregulation of proneural activity. Forced expression of Olig2 and Nkx2.2 is sufficient for ectopic induction of OLPs and production of oligodendrocytes. But in the wild-type embryo, the Olig2–Nkx2.2 interaction seems to be more relevant at later stages for promoting OLP maturation, rather than for the specification of OLPs. Neural specification in vivo is context-dependent and tightly linked to position within the developing CNS, but such anatomical and spatial constraints seem to be less relevant in culture. For example, in neurosphere assays, single neural stem cells from various dorsoventral levels of the CNS can behave as tripotent cells that give rise to neurons, astrocytes and oligodendrocytes. The availability of robust and specific markers for glial lineage development should facilitate assessment of the contributions of glia and their precursors to a range of human neurological disorders, including multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer's disease. Vertebrate macroglial cells have diverse roles in the maintenance of neurological function. This review highlights progress in our understanding of the mechanisms that underlie the specification of precursors for two key macroglial subtypes — oligodendrocytes and astrocytes — in the embryo. These mechanisms are strikingly similar to those that underlie the development of neuronal subtypes, including emergence from localized regions of the neural tube, and involvement of common signalling pathways and downstream transcription factors. The switch from neuronal to glial precursor production can be modelled as a complex interplay between regionally-restricted components and generalized temporal regulators.