The development of the nervous system is regulated by numerous intracellular molecules and cellular signals that interact temporally and spatially with the extracellular microenvironment. The three major cell types in the brain, i.e., neurons and two types of glial cells (astrocytes and oligodendrocytes), are generated from common multipotent neural stem cells (NSCs) throughout life. However, NSCs do not have this multipotentiality from the beginning. During cortical development, NSCs sequentially obtain abilities to differentiate into neurons and glial cells in response to combinations of spatiotemporally modulated cell-intrinsic epigenetic alterations and extrinsic factors. After the completion of brain development, a limited population of NSCs remains in the adult brain and continues to produce neurons (adult neurogenesis), thus contributing to learning and memory. Many biological aspects of brain development and adult neurogenesis are regulated by epigenetic changes via behavioral control of NSCs. Epigenetic dysregulation has also been implicated in the pathogenesis of various brain diseases. Here, we present recent advances in the epigenetic regulation of NSC behavior and its dysregulation in brain disorders.

Microglia are highly heterogeneous as resident immune cells in the central nervous system. Although the proinflammatory phenotype of microglia is driven by the metabolic transformation in the disease state, the mechanism of metabolic reprogramming in microglia and whether it affects surrounding astrocyte progenitors have not been well elucidated. Here, we illustrate the communication between microglial metabolism and astrogenesis during embryonic development. The transcription factor BTB and CNC homology 1 (Bach1) reduces lactate production by inhibiting two key enzymes, HK2 and GAPDH, during glycolysis. Metabolic perturbation of microglia reduces lactate-dependent histone modification enrichment at the Lrrc15 promoter. The microglia-derived LRRC15 interacts with CD248 to participate in the JAK/STAT pathway and influence astrogenesis. In addition, Bach1cKO-Cx3 mice exhibit abnormal neuronal differentiation and anxiety-like behaviors. Altogether, this work suggests that the maintenance of microglia metabolic homeostasis during early brain development is closely related to astrogenesis, providing insights into astrogenesis and related diseases.

Treatment with bexarotene, a selective retinoid X receptor (RXR) agonist, significantly improves behavioral dysfunctions in various neurodegenerative animal models. Additionally, it activates neurodevelopmental and plasticity pathways in the brains of adult mice. Our objective was to investigate the impact of RXR activation by bexarotene on adult neural stem cells (aNSC) and their cell lineages. To achieve this, we treated NSCs isolated from the subventricular zone (SVZ) of adult rat brains from the proliferative stage to the differentiated status. The results showed that bexarotene-treated aNSC exhibited increased BrdU incorporation, SOX2+ dividing cell pairs, and cell migration from neurospheres, revealing that the treatment promotes self-renewing proliferation and cell motility in SVZ-aNCS. Furthermore, bexarotene induced a cell fate shift characterized by a significant increase in GFAP+/S100B+ differentiated astrocytes, which uncovers the participation of activated-RXR in astrogenesis. In the neuronal lineage, the fate shift was counteracted by bexarotene-induced enhancement of NeuN+ nuclei together with neurite network outgrowth, indicating that the RXR agonist stimulates SVZ-aNCS neuronal differentiation at later stages. These findings establish new connections between RXR activation, astro- and neurogenesis in the adult brain, and contribute to the development of therapeutic strategies targeting nuclear receptors for neural repair.

Radiation therapy (RT) is a crucial treatment modality for central nervous system (CNS) tumors but toxicity to healthy CNS tissues remains a challenge. Additionally, environmental exposure to radiation during nuclear catastrophes or space travel presents a risk of CNS toxicity. However, the underlying mechanisms of radiation-induced CNS toxicity are not fully understood. Neural progenitor cells (NPCs) are highly radiosensitive, resulting in decreased neurogenesis in the hippocampus. This study aimed to characterize a novel platform utilizing rat NPCs cultured as 3D neurospheres (NSps) to screen the safety and efficacy of experimental drugs with and without radiation exposure. The effect of radiation on NSp growth and differentiation was assessed by measuring sphere volume and the expression of neuronal differentiation markers Nestin and GFAP and proliferation marker Ki67. Radiation exposure inhibited NSp growth, decreased proliferation, and increased GFAP expression, indicating astrocytic differentiation. RNA sequencing analysis supported these findings, showing upregulation of Notch, BMP2/4, S100b, and GFAP gene expression during astrogenesis. By recapitulating radiation-induced toxicity and astrocytic differentiation, this single-NSp culture system provides a high-throughput preclinical model for assessing the effects of various radiation modalities and evaluates the safety and efficacy of potential therapeutic interventions in combination with radiation.

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Within the developing cerebral cortex, neural stem cells (NSCs) give rise to neurons and glial cells, according to complex spatio-temporal trajectories. In this respect, a key issue is how NSCs are committed to different neural lineages in time and space. Clonal assays are a powerful tool to address this issue. Here we describe an easy clonal assay protocol employable to dissect NSCs lineage commitment and molecular mechanisms underlying it. NSCs of distinctive spatio-temporal origin, and/or having undergone different molecular manipulations, are plated at low density and allowed to differentiate for a few days. Then, systematic immunoprofiling of the resulting clones allows to quantify commitment of their NSC ancestors to neuronal and astroglial fates.

The vision of astroglia as a bare scaffold to neuronal circuitry has been largely overturned. Astrocytes exert a neurotrophic function, but also take active part in supporting synaptic transmission and in calibrating blood circulation. Many aspects of their functioning have been unveiled from studies conducted in murine models, however evidence is showing many differences between mouse and human astrocytes starting from their development and encompassing morphological, transcriptomic and physiological variations when they achieve complete maturation. The evolutionary race toward superior cognitive abilities unique to humans has drastically impacted neocortex structure and, together with neuronal circuitry, astrocytes have also been affected with the acquisition of species-specific properties. In this review, we summarize diversities between murine and human astroglia, with a specific focus on neocortex, in a panoramic view that starts with their developmental origin to include all structural and molecular differences that mark the uniqueness of human astrocytes.

Aquaporin 4 (AQP4) is a cerebral glial marker that labels ependymal cells and astrocytes\' endfeet and is the main water channel responsible for the parenchymal fluid balance. However, in brain development, AQP4 is a marker of glial stem cells and plays a crucial role in the pathophysiology of pediatric hydrocephalus. Gliogenesis characterization has been hampered by a lack of biomarkers for precursor and intermediate stages and a deeper understanding of hydrocephalus etiology is needed. This manuscript is a focused review of the current research landscape on AQP4 as a possible biomarker for gliogenesis and its influence in pediatric hydrocephalus, emphasizing reactive astrogliosis. The goal is to understand brain development under hydrocephalic and normal physiologic conditions.

Transcription factors with basic-helix-loop-helix (bHLH) motifs can control neural progenitor fate determination to neurons and oligodendrocytes. How bHLH transcription factors regulate astrogenesis remains largely unknown. Here, we report that NPAS3, a bHLH transcription factor, is a critical regulator of astrogenesis. Npas3 deficiency impairs cortical astrogenesis, correlating with abnormal brain development and autistic-like behaviors. Single-cell transcriptomes reveal that Npas3 knockout induces abnormal transition states in the differentiation trajectories from radial glia to astrocytes. Analysis of chromatin immunoprecipitation sequencing data in primary cortical astrocytes shows that NPAS3 binding targets are involved in functions of brain development and synapse organization. Co-culture assay further indicates that NPAS3-impaired astrogenesis induces synaptic deficits in wild-type neurons. Astrocyte-specific knockdown of NPAS3 in wild-type cortex causes synaptic and behavioral abnormalities associated with the core symptoms in autism. Together, our findings suggest that transcription factor NPAS3 regulates astrogenesis and its subsequent consequences for brain development and behavior.

Sizes of neuronal, astroglial and oligodendroglial complements forming the neonatal cerebral cortex largely depend on rates at which pallial stem cells give rise to lineage-committed progenitors and the latter ones progress to mature cell types. Here, we investigated the spatial articulation of pallial stem cells\' (SCs) commitment to astrogenesis as well as the progression of committed astroglial progenitors (APs) to differentiated astrocytes, by clonal and kinetic profiling of pallial precursors. We found that caudal-medial (CM) SCs are more prone to astrogenesis than rostro-lateral (RL) ones, while RL-committed APs are more keen to proliferate than CM ones. Next, we assessed the control of these phenomena by 2 key transcription factor genes mastering regionalization of the early cortical primordium, Emx2 and Foxg1, via lentiviral somatic transgenesis, epistasis assays, and ad hoc rescue assays. We demonstrated that preferential CM SCs progression to astrogenesis is promoted by Emx2, mainly via Couptf1, Nfia, and Sox9 upregulation, while Foxg1 antagonizes such progression to some extent, likely via repression of Zbtb20. Finally, we showed that Foxg1 and Emx2 may be implicated-asymmetrically and antithetically-in shaping distinctive proliferative/differentiative behaviors displayed by APs in hippocampus and neocortex.