The Genomic Intersection of Oligodendrocyte Dynamics in Schizophrenia and Aging Unravels Novel Pathological Mechanisms and Therapeutic Potentials.

Schizophrenia is a significant worldwide health concern, affecting over 20 million individuals and contributing to a potential reduction in life expectancy by up to 14.5 years. Despite its profound impact, the precise pathological mechanisms underlying schizophrenia continue to remain enigmatic, with previous research yielding diverse and occasionally conflicting findings. Nonetheless, one consistently observed phenomenon in brain imaging studies of schizophrenia patients is the disruption of white matter, the bundles of myelinated axons that provide connectivity and rapid signalling between brain regions. Myelin is produced by specialised glial cells known as oligodendrocytes, which have been shown to be disrupted in post-mortem analyses of schizophrenia patients. Oligodendrocytes are generated throughout life by a major population of oligodendrocyte progenitor cells (OPC), which are essential for white matter health and plasticity. Notably, a decline in a specific subpopulation of OPC has been identified as a principal factor in oligodendrocyte disruption and white matter loss in the aging brain, suggesting this may also be a factor in schizophrenia. In this review, we analysed genomic databases to pinpoint intersections between aging and schizophrenia and identify shared mechanisms of white matter disruption and cognitive dysfunction.

Myelin repair is fostered by the corticosteroid medrysone specifically acting on astroglial subpopulations.

BACKGROUND: Multiple sclerosis is characterised by inflammation, oligodendrocyte loss and axonal demyelination and shows an additional impact on astrocytes, and their polarization. Although a certain degree of spontaneous myelin repair can be observed, disease progression, and aging impair regeneration efforts highlighting the need to better understand glial cell dynamics to establish specific regenerative treatments. METHODS: Applying a chronic demyelination model, we here analysed demyelination and remyelination related effects on astrocytes and stem cell niches and studied the consequences of medrysone application on myelin repair, and astrocyte polarization. FINDINGS: Medrysone induced recovery of mature oligodendrocytes, myelin expression and node formation. In addition, C3d/S100a10 co-expression in astrocytes was enhanced. Moreover, Timp1 expression in C3d positive astrocytes revealed another astrocytic phenotype with a myelination promoting character. INTERPRETATION: Based on these findings, specific astrocyte subpopulations are suggested to act in a myelin regenerative way and manner the regulation of which can be positively modulated by this corticosteroid. FUNDING: This work was supported by the Jürgen Manchot Stiftung, the Research Commission of the medical faculty of the Heinrich-Heine-University of Düsseldorf, the Christiane and Claudia Hempel Foundation for clinical stem cell research and the James and Elisabeth Cloppenburg, Peek and Cloppenburg Düsseldorf Stiftung.

Targeting the Subventricular Zone to Promote Myelin Repair in the Aging Brain.

The subventricular zone (SVZ) is the largest and most active germinal zone in the adult forebrain. Neural stem cells (NSCs) of the SVZ generate olfactory interneurons throughout life and retain the intrinsic ability to generate oligodendrocytes (OLs), the myelinating cells of the central nervous system. OLs and myelin are targets in demyelinating diseases such as multiple sclerosis (MS). Remyelination is dependent on the ability of oligodendrocyte progenitor cells (OPCs) to proliferate, migrate, and terminally differentiate into myelinating OLs. During aging, there is a gradual decrease in the regenerative capacity of OPCs, and the consequent loss of OLs and myelin is a contributing factor in cognitive decline and the failure of remyelination in MS and other pathologies with aging contexts, including Alzheimer's disease (AD) and stroke. The age-related decrease in oligodendrogenesis has not been fully characterised but is known to reflect changes in intrinsic and environmental factors affecting the ability of OPCs to respond to pro-differentiation stimuli. Notably, SVZ-derived OPCs are an important source of remyelinating OLs in addition to parenchymal OPCs. In this mini-review, we briefly discuss differences between SVZ-derived and parenchymal OPCs in their responses to demyelination and highlight challenges associated with their study in vivo and how they can be targeted for regenerative therapies in the aged brain.

Epidermal Growth Factor Pathway in the Age-Related Decline of Oligodendrocyte Regeneration.

Oligodendrocytes (OLs) are specialized glial cells that myelinate CNS axons. OLs are generated throughout life from oligodendrocyte progenitor cells (OPCs) via a series of tightly controlled differentiation steps. Life-long myelination is essential for learning and to replace myelin lost in age-related pathologies such as Alzheimer's disease (AD) as well as white matter pathologies such as multiple sclerosis (MS). Notably, there is considerable myelin loss in the aging brain, which is accelerated in AD and underpins the failure of remyelination in secondary progressive MS. An important factor in age-related myelin loss is a marked decrease in the regenerative capacity of OPCs. In this review, we will contextualize recent advances in the key role of Epidermal Growth Factor (EGF) signaling in regulating multiple biological pathways in oligodendroglia that are dysregulated in aging.

C21orf91 Regulates Oligodendroglial Precursor Cell Fate-A Switch in the Glial Lineage?

Neuropathological diseases of the central nervous system (CNS) are frequently associated with impaired differentiation of the oligodendroglial cell lineage and subsequent alterations in white matter structure and dynamics. Down syndrome (DS), or trisomy 21, is the most common genetic cause for cognitive impairments and intellectual disability (ID) and is associated with a reduction in the number of neurons and oligodendrocytes, as well as with hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS and underestimated the role of glial cells as pathogenic players. This also relates to C21ORF91, a protein considered a key modulator of aberrant CNS development in DS. We investigated the role of C21orf91 ortholog in terms of oligodendrogenesis and myelination using database information as well as through cultured primary oligodendroglial precursor cells (OPCs). Upon modulation of C21orf91 gene expression, we found this factor to be important for accurate oligodendroglial differentiation, influencing their capacity to mature and to myelinate axons. Interestingly, C21orf91 overexpression initiates a cell population coexpressing astroglial- and oligodendroglial markers indicating that elevated C21orf91 expression levels induce a gliogenic shift towards the astrocytic lineage reflecting non-equilibrated glial cell populations in DS brains.

Keeping the ageing brain wired: a role for purine signalling in regulating cellular metabolism in oligodendrocyte progenitors.

White matter (WM) is a highly prominent feature in the human cerebrum and is comprised of bundles of myelinated axons that form the connectome of the brain. Myelin is formed by oligodendrocytes and is essential for rapid neuronal electrical communication that underlies the massive computing power of the human brain. Oligodendrocytes are generated throughout life by oligodendrocyte precursor cells (OPCs), which are identified by expression of the chondroitin sulphate proteoglycan NG2 (Cspg4), and are often termed NG2-glia. Adult NG2+ OPCs are slowly proliferating cells that have the stem cell-like property of self-renewal and differentiation into a pool of 'late OPCs' or 'differentiation committed' OPCs(COPs) identified by specific expression of the G-protein-coupled receptor GPR17, which are capable of differentiation into myelinating oligodendrocytes. In the adult brain, these reservoirs of OPCs and COPs ensure rapid myelination of new neuronal connections formed in response to neuronal signalling, which underpins learning and cognitive function. However, there is an age-related decline in myelination that is associated with a loss of neuronal function and cognitive decline. The underlying causes of myelin loss in ageing are manifold, but a key factor is the decay in OPC 'stemness' and a decline in their replenishment of COPs, which results in the ultimate failure of myelin regeneration. These changes in ageing OPCs are underpinned by dysregulation of neuronal signalling and OPC metabolic function. Here, we highlight the role of purine signalling in regulating OPC self-renewal and the potential importance of GPR17 and the P2X7 receptor subtype in age-related changes in OPC metabolism. Moreover, age is the main factor in the failure of myelination in chronic multiple sclerosis and myelin loss in Alzheimer's disease, hence understanding the importance of purine signalling in OPC regeneration and myelination is critical for developing new strategies for promoting repair in age-dependent neuropathology.

Functional genomic analyses highlight a shift in Gpr17-regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum.

Brain ageing is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age-related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to ageing as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain ageing hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrate that oligodendroglial and myelin genes are amongst the most altered in the ageing mouse cerebrum. This was underscored by the identification of causal links between signalling pathways and their downstream transcriptional networks that define oligodendroglial disruption in ageing. The results highlighted that the G-protein coupled receptor Gpr17 is central to the disruption of OPCs in ageing and this was confirmed by genetic fate-mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPCs and restore myelination in age-related neuropathological contexts.

A gene regulatory architecture that controls region-independent dynamics of oligodendrocyte differentiation.

Oligodendrocytes (OLs) facilitate information processing in the vertebrate central nervous system via axonal ensheathment. The structure and dynamics of the regulatory network that mediates oligodendrogenesis are poorly understood. We employed bioinformatics and meta-analysis of high-throughput datasets to reconstruct a regulatory network underpinning OL differentiation. From this network, we identified families of feedforward loops comprising the transcription factors (TFs) Olig2, Sox10, and Tcf7l2 and their targets. Among the targets, we found eight other TFs related to OL differentiation, suggesting a hierarchical architecture in which some TFs (Olig2, Sox10, and Tcf7l2) regulate via feedforward loops the expression of others (Sox2, Sox6, Sox11, Nkx2-2, Nkx6-2, Hes5, Myt1, and Myrf). Model simulations with a kinetic model reproduced the mechanisms of OL differentiation only when in the model, Sox10-mediated repression of Tcf7l2 by miR-338/miR-155 was introduced, a prediction confirmed in genetic functional experiments. Additional model simulations suggested that OLs from dorsal regions emerge through BMP/Sox9 signaling.

HOPX Defines Heterogeneity of Postnatal Subventricular Zone Neural Stem Cells.

The largest diversity of neural lineages generated from the subventricular zone (SVZ) occurs early after birth and is regulated in a spatiotemporal manner depending on the expression of specific transcriptional cues. Transcriptomics and fate-mapping approaches were employed to explore the relationship between regional expression of transcription factors by neural stem cells (NSCs) and the specification of distinct neural lineages. Our results support an early priming of NSCs for the genesis of defined cell types depending on their spatial location in the SVZ and identify HOPX as a marker of a subpopulation primed toward astrocytic fates. Manipulation of HOPX expression, however, showed no effect on astrogenesis but resulted in marked changes in the number of NSCs and of their progenies. Taken together, our results highlight transcriptional and spatial heterogeneity of postnatal NSCs and reveal a key role for HOPX in controlling SVZ germinal activity.

A dual role for the transcription factor Sp8 in postnatal neurogenesis.

Neural stem cells (NSCs) of the postnatal subventricular zone (SVZ) continue producing distinct subtypes of olfactory bulb (OB) interneurons throughout life. Understanding the transcriptional coding of this diversity remains a great challenge of modern neurosciences. Interneurons expressing calretinin (CalR) represent the main interneuron subtype produced in the glomerular cell layer (GL) after birth. Previous studies have suggested that their specification relies on expression of the transcription factor Sp8 by SVZ NSCs. In this study, we performed fate mapping of NSCs that generate CalR+ or non-CalR+ interneurons, in order to assess the pattern of Sp8 expression during postnatal neurogenesis. We highlight a complex pattern of Sp8 expression, which appears to be expressed in all interneurons lineages, before getting gradually restricted to maturing CalR+ interneurons. To decipher the early and late functions of Sp8 in postnatal OB neurogenesis, we combined transient, permanent and conditional genetic approaches to manipulate Sp8 at distinct neurogenic stages. While Sp8 plays an early role in controlling proliferation in all lineages, it is not involved in the early specification of CalR+ periglomerular interneurons, but plays a crucial role in their long term survival. Together, our results highlight a crucial and dual role for Sp8 during postnatal neurogenesis.

Transcriptional Profiling of Ligand Expression in Cell Specific Populations of the Adult Mouse Forebrain That Regulates Neurogenesis.

In the adult central nervous system (CNS), the subventricular zone (SVZ) of the forebrain is the largest and most active source of neural stem cells (NSCs) that generates mainly neurons and few glial cells lifelong. A large body of evidence has shed light on the distinct families of signaling ligands (i.e., morphogens, growth factors, secreted molecules that alter signaling pathways) in regulating NSC biology. However, most of the research has focused on the mRNA expression of individual or few signaling ligands and their pathway components in specific cell types of the CNS in the context of neurogenesis. A single unifying study that underlines the expression of such molecules comprehensively in different cell types in spatial contexts has not yet been reported. By using whole genome transcriptome datasets of individual purified cell specific populations of the adult CNS, the SVZ niche, NSCs, glial cells, choroid plexus, and performing a bioinformatic meta-analysis of signaling ligands, their expression in the forebrain was uncovered. Therein, we report that a large plethora of ligands are abundantly expressed in the SVZ niche, largely from the vasculature than from other sources that may regulate neurogenesis. Intriguingly, this sort of analysis revealed a number of ligands with unknown functions in neurogenesis contexts that warrants further investigations. This study therefore serves as a framework for investigators in the field for understanding the expression patterns of signaling ligands and pathways regulating neurogenesis.

Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity.

Strategies for promoting neural regeneration are hindered by the difficulty of manipulating desired neural fates in the brain without complex genetic methods. The subventricular zone (SVZ) is the largest germinal zone of the forebrain and is responsible for the lifelong generation of interneuron subtypes and oligodendrocytes. Here, we have performed a bioinformatics analysis of the transcriptome of dorsal and lateral SVZ in early postnatal mice, including neural stem cells (NSCs) and their immediate progenies, which generate distinct neural lineages. We identified multiple signaling pathways that trigger distinct downstream transcriptional networks to regulate the diversity of neural cells originating from the SVZ. Next, we used a novel in silico genomic analysis, searchable platform-independent expression database/connectivity map (SPIED/CMAP), to generate a catalogue of small molecules that can be used to manipulate SVZ microdomain-specific lineages. Finally, we demonstrate that compounds identified in this analysis promote the generation of specific cell lineages from NSCs in vivo, during postnatal life and adulthood, as well as in regenerative contexts. This study unravels new strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases.

Taking Advantage of Nature's Gift: Can Endogenous Neural Stem Cells Improve Myelin Regeneration?

Irreversible functional deficits in multiple sclerosis (MS) are directly correlated to axonal damage and loss. Neurodegeneration results from immune-mediated destruction of myelin sheaths and subsequent axonal demyelination. Importantly, oligodendrocytes, the myelinating glial cells of the central nervous system, can be replaced to some extent to generate new myelin sheaths. This endogenous regeneration capacity has so far mainly been attributed to the activation and recruitment of resident oligodendroglial precursor cells. As this self-repair process is limited and increasingly fails while MS progresses, much interest has evolved regarding the development of remyelination-promoting strategies and the presence of alternative cell types, which can also contribute to the restoration of myelin sheaths. The adult brain comprises at least two neurogenic niches harboring life-long adult neural stem cells (NSCs). An increasing number of investigations are beginning to shed light on these cells under pathological conditions and revealed a significant potential of NSCs to contribute to myelin repair activities. In this review, these emerging investigations are discussed with respect to the importance of stimulating endogenous repair mechanisms from germinal sources. Moreover, we present key findings of NSC-derived oligodendroglial progeny, including a comprehensive overview of factors and mechanisms involved in this process.

Mosaic Subventricular Origins of Forebrain Oligodendrogenesis.

In the perinatal as well as the adult CNS, the subventricular zone (SVZ) of the forebrain is the largest and most active source of neural stem cells (NSCs) that generates neurons and oligodendrocytes (OLs), the myelin forming cells of the CNS. Recent advances in the field are beginning to shed light regarding SVZ heterogeneity, with the existence of spatially segregated microdomains that are intrinsically biased to generate phenotypically distinct neuronal populations. Although most research has focused on this regionalization in the context of neurogenesis, newer findings underline that this also applies for the genesis of OLs under the control of specific patterning molecules. In this mini review, we discuss the origins as well as the mechanisms that induce and maintain SVZ regionalization. These come in the flavor of specific signaling ligands and subsequent initiation of transcriptional networks that provide a basis for subdividing the SVZ into distinct lineage-specific microdomains. We further emphasize canonical Wnts and FGF2 as essential signaling pathways for the regional genesis of OL progenitors from NSCs of the dorsal SVZ. This aspect of NSC biology, which has so far received little attention, may unveil new avenues for appropriately recruiting NSCs in demyelinating diseases.

Septo-temporal distribution and lineage progression of hippocampal neurogenesis in a primate (Callithrix jacchus) in comparison to mice.

Adult born neurons in the hippocampus show species-specific differences in their numbers, the pace of their maturation and their spatial distribution. Here, we present quantitative data on adult hippocampal neurogenesis in a New World primate, the common marmoset (Callithrix jacchus) that demonstrate parts of the lineage progression and age-related changes. Proliferation was largely (∼70%) restricted to stem cells or early progenitor cells, whilst the remainder of the cycling pool could be assigned almost exclusively to Tbr2+ intermediate precursor cells in both neonate and adult animals (20-122 months). Proliferating DCX+ neuroblasts were virtually absent in adults, although rare MCM2+/DCX+ co-expression revealed a small, persisting proliferative potential. Co-expression of DCX with calretinin was very limited in marmosets, suggesting that these markers label distinct maturational stages. In adult marmosets, numbers of MCM2+, Ki67+, and significantly Tbr2+, DCX+, and CR+ cells declined with age. The distributions of granule cells, proliferating cells and DCX+ young neurons along the hippocampal longitudinal axis were equal in marmosets and mice. In both species, a gradient along the hippocampal septo-temporal axis was apparent for DCX+ and resident granule cells. Both cell numbers are higher septally than temporally, whilst proliferating cells were evenly distributed along this axis. Relative to resident granule cells, however, the ratio of proliferating cells and DCX+ neurons remained constant in the septal, middle, and temporal hippocampus. In marmosets, the extended phase of the maturation of young neurons that characterizes primate hippocampal neurogenesis was due to the extension in a large CR+/DCX- cell population. This clear dissociation between DCX+ and CR+ young neurons has not been reported for other species and may therefore represent a key primate-specific feature of adult hippocampal neurogenesis.

Adding a spatial dimension to postnatal ventricular-subventricular zone neurogenesis.

Neurogenesis does not stop abruptly at birth, but persists in specific brain regions throughout life. The neural stem cells (NSCs) located in the largest germinal region of the forebrain, the ventricular-subventricular zone (V-SVZ), replenish olfactory neurons throughout life. However, V-SVZ NSCs are heterogeneous: they have different embryonic origins and give rise to distinct neuronal subtypes depending on their location. In this Review, we discuss how this spatial heterogeneity arises, how it affects NSC biology, and why its consideration in future studies is crucial for understanding general principles guiding NSC self-renewal, differentiation and specification.

Transcriptional Hallmarks of Heterogeneous Neural Stem Cell Niches of the Subventricular Zone.

Throughout postnatal life in mammals, neural stem cells (NSCs) are located in the subventricular zone (SVZ) of the lateral ventricles. The greatest diversity of neuronal and glial lineages they generate occurs during early postnatal life in a region-specific manner. In order to probe heterogeneity of the postnatal SVZ, we microdissected its dorsal and lateral walls at different postnatal ages and isolated NSCs and their immediate progeny based on their expression of Hes5-EGFP/Prominin1 and Ascl1-EGFP, respectively. Whole genome comparative transcriptome analysis revealed transcriptional regulators as major hallmarks that sustain postnatal SVZ regionalization. Manipulation of single genes encoding for locally enriched transcription factors (loss-of-function or ectopic gain-of-function in vivo) influenced NSC specification indicating that the fate of regionalized postnatal SVZ-NSCs can be readily modified. These findings reveal the pronounced transcriptional heterogeneity of the postnatal SVZ and provide targets to recruit region-specific lineages in regenerative contexts. Stem Cells 2015;33:2232-2242.