Mouse Subventricular Zone Research Articles

Stanniocalcin 2 Promotes Neuronal Differentiation in Neural Stem/Progenitor Cells of the Mouse Subventricular Zone Through Activation of AKT Pathway.

Neural stem/progenitor cells (NSPCs) persist in the mammalian subventricular zone (SVZ) throughout life, responding to various pathophysiological stimuli and playing a crucial role in central nervous system repair. Although numerous studies have elucidated the role of stanniocalcin 2 (STC2) in regulating cell differentiation processes, its specific function in NSPCs differentiation remains poorly understood. Clarifying the role of STC2 in NSPCs is essential for devising novel strategies to enhance the intrinsic potential for brain regeneration postinjury. Our study revealed the expression of STC2 in NSPCs derived from the SVZ of the C57BL/6N mouse. In cultured SVZ-derived NSPCs, STC2 treatment significantly increased the number of Tuj1 and DCX-positive cells. Furthermore, STC2 injection into the lateral ventricle promoted the neuronal differentiation of NSPCs and migration to the olfactory bulb. Conversely, the STC2 knockdown produced the opposite effect. Further investigation showed that STC2 treatment enhanced AKT phosphorylation in cultured NSPCs, whereas STC2 inhibition hindered AKT activation. Notably, the neuronal differentiation induced by STC2 was blocked by the AKT inhibitor GSK690693, whereas the AKT activator SC79 reversed the impact of STC2 knockdown on neuronal differentiation. Our findings indicate that enhancing STC2 expression in SVZ-derived NSPCs facilitates neuronal differentiation, with AKT regulation potentially serving as a key intracellular target of STC2 signaling.

The effects of Atoh8 on postnatal murine neurogenesis.

Introduction Basic helix-loop-helix (bHLH) transcription factors are expressed in various organs and are involved in diverse developmental processes. The mouse atonal homolog 8 (Atoh8), a bHLH transcription factor plays a crucial role in various developmental processes, especially as a regulator of neurogenesis in the retina. Besides, Atoh8 expression has been observed in the central nervous system. The function of Atoh8 during the postnatal neurogenesis is still unclear. Methods This study focuses on elucidating the impact of Atoh8 on postnatal neurogenesis in the brain, particularly in selected regions; the subventricular zone (SVZ), rostral migration stream (RMS) and olfactory bulb (OB), across different life stages, using male homozygous Atoh8-knockout (M6KO) mice. Our morphometric analysis is based on immunohistochemically labeled markers for neuroblasts (Doublecortin) and proliferation (Phospho-Histone H3, PHH3) as well as pan neuronal markers. Results In Atoh8-/- mice alteration in the postnatal neurogenesis can be observed. Immunohistochemical analysis revealed a significant reduction in doublecortin-positive neuroblasts within the SVZ of neonatal M6KO mice compared to wildtype (WT) mice. Interestingly, no differences in cell number and distribution was observed in the subsequent migration of neuroblasts through the rostral migration stream (RMS) to the olfactory bulb (OB). Proliferating PHH3-positive neuronal progenitor cells were significantly diminished in proliferation rate in both the SVZ and RMS of neonatal and young M6KO mice. Furthermore, in the glomerular layer of the OB significantly fewer neurons were detected in the neonatal stage. Conclusion In conclusion, Atoh8 emerges as a positive regulator of postnatal neurogenesis in the brain. Its role encompasses the promotion of neuroblast formation, modulation of proliferation rates, differentiation, and maintenance of mature neurons. Understanding the intricacies of Atoh8 function provides valuable insights into the complex regulatory mechanisms governing neurogenesis.

Morphological classification of radial glia-like cells in the postnatal mouse subventricular zone.

The subventricular zone (SVZ) is one of the neurogenic regions of the adult mammalian brain. Neural stem cells (NSCs) in the SVZ have certain key features: they express glial fibrillary acidic protein (GFAP), proliferate slowly, have a radial glia-like (RG-L) morphology, and are in contact with the cerebrospinal fluid (CSF). NSCs have been isolated by FACS to analyse them, but their morphology has not been systematically examined. To address this knowledge gap, we sparsely labelled RG-L cells in the SVZ of neonatal mice by introducing via electroporation a plasmid expressing fluorescent protein under the control of the GFAP promoter. We then classified RG-L cells into three types (RG-L1, 2, and 3) based on their morphologies. RG-L1 cells had a basal process with some branches and numerous fine processes. RG-L2 cells had a basal process, but fewer branches and fine processes than RG-L1 cells. RG-L3 cells had one basal process that was almost free of branches and fine processes. Importantly, regardless of the cell type, about half of their somata resided on the basal side of the SVZ. Based on changes in their proportions during postnatal development and their expression of GFAP and cell proliferation markers at the adult stage, we speculated that NSCs change their morphologies during development/maturation and not all NSCs must always be in the apical SVZ or in contact with the CSF. Our results indicate that in addition to expression of markers for NSCs, the morphology is a critical feature to identify NSCs.

Combined deletion of Mct8 and Dio2 impairs SVZ neurogliogenesis and olfactory function in adult mice

Within the adult mouse subventricular zone (SVZ), neural stem cells (NSCs) produce neuroblasts and oligodendrocyte precursor cells (OPCs). T3, the active thyroid hormone, influences renewal and commitment of SVZ progenitors. However, how regulators of T3 availability affect these processes is less understood. Using Mct8/Dio2 knockout mice, we investigated the role of MCT8, a TH transporter, and DIO2, the T3-generating enzyme, in regulating adult SVZ-neurogliogenesis. Single-cell RNA-Seq revealed Mct8 expression in various SVZ cell types in WT mice, while Dio2 was enriched in neurons, astrocytes, and quiescent NSCs. The absence of both regulators in the knockout model dysregulated gene expression, increased the neuroblast/OPC ratio and hindered OPC differentiation. Immunostainings demonstrated compromised neuroblast migration reducing their supply to the olfactory bulbs, impairing interneuron differentiation and odor discrimination. These findings underscore the pivotal roles of MCT8 and DIO2 in neuro- and oligodendrogenesis, offering targets for therapeutic avenues in neurodegenerative and demyelinating diseases.

Cytotoxicity of amine-modified polystyrene MPs and NPs on neural stem cells cultured from mouse subventricular zone

Microplastics (MPs) and nanoplastics (NPs) are found in various environments such as aquatic, terrestrial, and aerial areas. Once ingested and inhaled, these tiny plastic debris damaged the digestive and respiratory organ systems in animals. In humans, the possible connection between MPs and various diseases such as lung diseases has been raised. Yet, the impact of MPs on the human nervous system has been unclear. Previous research using animals and cultured cells showed possible neurotoxicity of MPs and NPs. In this study, we used neural stem cells cultured from mouse subventricular zone to examine the effects of polystyrene (PS) NPs and MPs with sizes of 0.1 μm, 1 μm, and 2 μm on the cell proliferation and differentiation. We observed that only positively charged NPs and MPs, but not negatively charged ones, decreased cell viability and proliferation. These amine-modified NPs and MPs decreased both neurogenesis and oligodendrogenesis. Finally, fully differentiated neurons and oligodendrocytes were damaged and removed by the application of NPs and MPs. All these effects varied among different sizes of NPs and MPs, with the greatest effects from 1 μm and the least effects from 2 μm. These results clearly demonstrate the cytotoxicity and neurotoxicity of PS-NPs and MPs.

Lineage-specific changes in mitochondrial properties during neural stem cell differentiation.

Neural stem cells (NSCs) reside in discrete regions of the adult mammalian brain where they can differentiate into neurons, astrocytes, and oligodendrocytes. Several studies suggest that mitochondria have a major role in regulating NSC fate. Here, we evaluated mitochondrial properties throughout NSC differentiation and in lineage-specific cells. For this, we used the neurosphere assay model to isolate, expand, and differentiate mouse subventricular zone postnatal NSCs. We found that the levels of proteins involved in mitochondrial fusion (Mitofusin [Mfn] 1 and Mfn 2) increased, whereas proteins involved in fission (dynamin-related protein 1 [DRP1]) decreased along differentiation. Importantly, changes in mitochondrial dynamics correlated with distinct patterns of mitochondrial morphology in each lineage. Particularly, we found that the number of branched and unbranched mitochondria increased during astroglial and neuronal differentiation, whereas the area occupied by mitochondrial structures significantly reduced with oligodendrocyte maturation. In addition, comparing the three lineages, neurons revealed to be the most energetically flexible, whereas astrocytes presented the highest ATP content. Our work identified putative mitochondrial targets to enhance lineage-directed differentiation of mouse subventricular zone-derived NSCs.

TRIP6 promotes neural stem cell maintenance through YAP-mediated Sonic Hedgehog activation.

In the adult mammalian brain, new neurons are continuously generated from neural stem cells (NSCs) in the subventricular zone (SVZ)-olfactory bulb (OB) pathway. YAP, a transcriptional co-activator of the Hippo pathway, promotes cell proliferation and inhibits differentiation in embryonic neural progenitors. However, the role of YAP in postnatal NSCs remains unclear. Here, we showed that YAP was present in NSCs of the postnatal mouse SVZ. Forced expression of Yap promoted NSC maintenance and inhibited differentiation, whereas depletion of Yap by RNA interference or conditional knockout led to the decline of NSC maintenance, premature neuronal differentiation, and collapse of neurogenesis. For the molecular mechanism, thyroid hormone receptor-interacting protein 6 (TRIP6) recruited protein phosphatase PP1A to dephosphorylate LATS1/2, therefore inducing YAP nuclear localization and activation. Moreover, TRIP6 promoted NSC maintenance, cell proliferation, and inhibited differentiation through YAP. In addition, YAP regulated the expression of the Sonic Hedgehog (SHH) pathway effector Gli2 and Gli1/2 mediated the effect of YAP on NSC maintenance. Together, our findings demonstrate a novel TRIP6-YAP-SHH axis, which is critical for regulating postnatal neurogenesis in the SVZ-OB pathway.

Inhibition of HDAC8 Reduces the Proliferation of Adult Neural Stem Cells in the Subventricular Zone.

In the adult mammalian brain, neurons are produced from neural stem cells (NSCs) residing in two niches-the subventricular zone (SVZ), which forms the lining of the lateral ventricles, and the subgranular zone in the hippocampus. Epigenetic mechanisms contribute to maintaining distinct cell fates by suppressing gene expression that is required for deciding alternate cell fates. Several histone deacetylase (HDAC) inhibitors can affect adult neurogenesis in vivo. However, data regarding the role of specific HDACs in cell fate decisions remain limited. Herein, we demonstrate that HDAC8 participates in the regulation of the proliferation and differentiation of NSCs/neural progenitor cells (NPCs) in the adult mouse SVZ. Specific knockout of Hdac8 in NSCs/NPCs inhibited proliferation and neural differentiation. Treatment with the selective HDAC8 inhibitor PCI-34051 reduced the neurosphere size in cultures from the SVZ of adult mice. Further transcriptional datasets revealed that HDAC8 inhibition in adult SVZ cells disturbs biological processes, transcription factor networks, and key regulatory pathways. HDAC8 inhibition in adult SVZ neurospheres upregulated the cytokine-mediated signaling and downregulated the cell cycle pathway. In conclusion, HDAC8 participates in the regulation of in vivo proliferation and differentiation of NSCs/NPCs in the adult SVZ, which provides insights into the underlying molecular mechanisms.

TISSUE: uncertainty-calibrated prediction of single-cell spatial transcriptomics improves downstream analyses.

Whole-transcriptome spatial profiling of genes at single-cell resolution remains a challenge. To address this limitation, spatial gene expression prediction methods have been developed to infer the spatial expression of unmeasured transcripts, but the quality of these predictions can vary greatly. Here we present Transcript Imputation with Spatial Single-cell Uncertainty Estimation (TISSUE) as a general framework for estimating uncertainty for spatial gene expression predictions and providing uncertainty-aware methods for downstream inference. Leveraging conformal inference, TISSUE provides well-calibrated prediction intervals for predicted expression values across 11 benchmark datasets. Moreover, it consistently reduces the false discovery rate for differential gene expression analysis, improves clustering and visualization of predicted spatial transcriptomics and improves the performance of supervised learning models trained on predicted gene expression profiles. Applying TISSUE to a MERFISH spatial transcriptomics dataset of the adult mouse subventricular zone, we identified subtypes within the neural stem cell lineage and developed subtype-specific regional classifiers.

Rbm24/Notch1 signaling regulates adult neurogenesis in the subventricular zone and mediates Parkinson-associated olfactory dysfunction.

Rationale: Adult neurogenesis in the subventricular zone (SVZ) is essential for maintaining neural homeostasis, and its dysregulation contributes to anosmia and delayed tissue healing in neurological disorders, such as Parkinson's disease (PD). Despite intricate regulatory networks identified in SVZ neurogenesis, the molecular mechanisms dynamically maintaining neural stem/progenitor cells (NSPCs) in response to physiological and pathological stimuli remain incompletely elucidated. Methods: We generated an RNA binding motif protein 24 (Rbm24) knockout model to investigate its impact on adult neurogenesis in the SVZ, employing immunofluorescence, immunoblot, electrophysiology, RNA-sequencing, and in vitro experiments. Further investigations utilized a PD mouse model, along with genetic and pharmacological manipulations, to elucidate Rbm24 involvement in PD pathology. Results: Rbm24, a multifaceted post-transcriptional regulator of cellular homeostasis, exhibited broad expression in the SVZ from development to aging. Deletion of Rbm24 significantly impaired NSPC proliferation in the adult SVZ, ultimately resulting in collapsed neurogenesis in the olfactory bulb. Notably, Rbm24 played a specific role in maintaining Notch1 mRNA stability in adult NSPCs. The Rbm24/Notch1 signaling axis was significantly downregulated in the SVZ of PD mice. Remarkably, overexpression of Rbm24 rescued disruption of adult neurogenesis and olfactory dysfunction in PD mice, and these effects were hindered by DAPT, a potent inhibitor of Notch1. Conclusions: Our findings highlight the critical role of the Rbm24/Notch1 signaling axis in regulating adult SVZ neurogenesis under physiological and pathological circumstances. This provides valuable insights into the dynamic regulation of NSPC homeostasis and offers a potential targeted intervention for PD and related neurological disorders.

Differential contribution of TrkB and p75NTR to BDNF-dependent self-renewal, proliferation, and differentiation of adult neural stem cells.

Alterations in adult neurogenesis are a common hallmark of neurodegenerative diseases. Therefore, understanding the molecular mechanisms that control this process is an indispensable requirement for designing therapeutic interventions addressing neurodegeneration. Neurotrophins have been implicated in multiple functions including proliferation, survival, and differentiation of the neural stem cells (NSCs), thereby being good candidates for therapeutic intervention. Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family and has been proven to promote neurogenesis in the subgranular zone. However, the effects of BDNF in the adult subventricular zone (SVZ) still remain unclear due to contradictory results. Using in vitro cultures of adult NSCs isolated from the mouse SVZ, we show that low concentrations of BDNF are able to promote self-renewal and proliferation in these cells by activating the tropomyosin-related kinase B (TrkB) receptor. However, higher concentrations of BDNF that can bind the p75 neurotrophin receptor (p75NTR) potentiate TrkB-dependent self-renewal and proliferation and promote differentiation of the adult NSCs, suggesting different molecular mechanisms in BDNF-promoting proliferation and differentiation. The use of an antagonist for p75NTR reduces the increment in NSC proliferation and commitment to the oligodendrocyte lineage. Our data support a fundamental role for both receptors, TrkB and p75NTR, in the regulation of NSC behavior.

Astragalus polysaccharides promote neural stem cells-derived oligodendrogenesis through attenuating CD8+T cell infiltration in experimental autoimmune encephalomyelitis

Endogenous neural stem cells (NSCs) have the potential to generate remyelinating oligodendrocytes, which play an important role in multiple sclerosis (MS). However, the differentiation of NSCs into oligodendrocytes is insufficient, which is considered a major cause of remyelination failure. Our previous work reported that Astragalus polysaccharides (APS) had a neuroprotective effect on experimental autoimmune encephalomyelitis (EAE) mice. However, it remains unclear whether APS regulate NSCs differentiation in EAE mice. In this study, our data illustrated that APS administration could promote NSCs in the subventricular zone (SVZ) to differentiate into oligodendrocytes. Furthermore, we found that APS significantly improved neuroinflammation and inhibited CD8+T cell infiltration into SVZ of EAE mice. We also found that MOG35-55-specific CD8+T cells suppressed NSCs differentiation into oligodendrocytes by secreting IFN-γ, and APS facilitated the differentiation of NSCs into oligodendrocytes which was related to decreased IFN-γ secretion. In addition, APS treatment did not show a better effect on the NSCs-derived oligodendrogenesis after CD8+T cell depletion. This present study demonstrated that APS alleviated neuroinflammation and CD8+T cell infiltration into SVZ to induce oligodendroglial differentiation, and thus exerted neuroprotective effect. Our findings revealed that reducing the infiltration of CD8+T cells might contribute to enhancing NSCs-derived neurogenesis. And APS might be a promising drug candidate to treat MS.

PDGFR-beta signaling mediates endogenous neurogenesis after postischemic neural stem/progenitor cell transplantation in mice

ABSTRACT Objective Although platelet-derived growth factor receptor (PDGFR)-β mediates the self-renewal and multipotency of neural stem/progenitor cells (NSPCs) in vitro and in vivo, its mechanisms of activating endogenous NSPCs following ischemic stroke still remain unproven. Methods The exogenous NSPCs were transplanted into the ischemic striatum of PDGFR-β conditionally neuroepithelial knockout (KO) mice at 24 h after transient middle cerebral artery occlusion (tMCAO). 5-Bromo-2’-deoxyuridine (BrdU) was intraperitoneally injected to label the newly formed endogenous NSPCs. Infarction volume was measured, and behavioral tests were performed. In the subventricular zone (SVZ), proliferation of endogenous NSPCs was tested, and synapse formation and expression of nutritional factors were measured. Results Compared with control mice, KO mice showed larger infarction volume, delayed neurological recovery, reduced numbers of BrdU positive cells, decreased expression of neurogenic factors (including neurofilament, synaptophysin, and brain-derived neurotrophic factor), and decreased synaptic regeneration in SVZ after tMCAO. Moreover, exogenous NSPC transplantation significantly alleviated neurologic dysfunction, promoted neurogenesis, increased expression of neurologic factors, and diminished synaptic deformation in SVZ of FL mice after tMCAO but had no beneficial effect in KO mice. Conclusion PDGFR-β signaling may promote activation of endogenous NSPCs after postischemic NSPC transplantation, and thus represents a novel potential regeneration-based therapeutic target.

Adipose transplantation improves olfactory function and neurogenesis via PKCα-involved lipid metabolism in Seipin Knockout mice

BackgroundLipodystrophy-associated metabolic disorders caused by Seipin deficiency lead to not only severe lipodystrophy but also neurological disorders. However, the underlying mechanism of Seipin deficiency-induced neuropathy is not well elucidated, and the possible restorative strategy needs to be explored.MethodsIn the present study, we used Seipin knockout (KO) mice, combined with transcriptome analysis, mass spectrometry imaging, neurobehavior test, and cellular and molecular assay to investigate the systemic lipid metabolic abnormalities in lipodystrophic mice model and their effects on adult neurogenesis in the subventricular zone (SVZ) and olfactory function. After subcutaneous adipose tissue (AT) transplantation, metabolic and neurological function was measured in Seipin KO mice to clarify whether restoring lipid metabolic homeostasis would improve neurobehavior.ResultsIt was found that Seipin KO mice presented the ectopic accumulation of lipids in the lateral ventricle, accompanied by decreased neurogenesis in adult SVZ, diminished new neuron formation in the olfactory bulb, and impaired olfactory-related memory. Transcriptome analysis showed that the differentially expressed genes (DEGs) in SVZ of adult Seipin KO mice were significantly enriched in lipid metabolism. Mass spectrometry imaging showed that the levels of glycerophospholipid and diglyceride (DG) were significantly increased. Furthermore, we found that AT transplantation rescued the abnormality of peripheral metabolism in Seipin KO mice and ameliorated the ectopic lipid accumulation, concomitant with restoration of the SVZ neurogenesis and olfactory function. Mechanistically, PKCα expression was up-regulated in SVZ tissues of Seipin KO mice, which may be a potential mediator between lipid dysregulation and neurological disorder. DG analogue (Dic8) can up-regulate PKCα and inhibit the proliferation and differentiation of neural stem cells (NSCs) in vitro, while PKCα inhibitor can block this effect.ConclusionThis study demonstrates that Seipin deficiency can lead to systemic lipid disorder with concomitant SVZ neurogenesis and impaired olfactory memory. However, AT restores lipid homeostasis and neurogenesis. PKCα is a key mediator mediating Seipin KO-induced abnormal lipid metabolism and impaired neurogenesis in the SVZ, and inhibition of PKCα can restore the impaired neurogenesis. This work reveals the underlying mechanism of Seipin deficiency-induced neurological dysfunction and provides new ideas for the treatment of neurological dysfunction caused by metabolic disorders.

Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors

In the adult mouse brain, the subventricular zone (SVZ) underlying the lateral ventricles harbours a population of quiescent neural stem cells, which can be activated (aNSCs) to initiate proliferation and generate a neurogenic lineage consisting of transit amplifying progenitors (TAPs), neuroblasts (NBs) and newborn neurons. This process is markedly reduced during aging. Recent studies suggest that the aged SVZ niche decreases the pool of proliferating neural/stem progenitor cells (NSPCs), and hence adult neurogenesis, by causing transcriptomic changes that promote NSC quiescence. The transcription factors that mediate these changes, however, remain unclear. We previously found that the homeobox gene Dbx2 is upregulated in NSPCs of the aged mouse SVZ and can inhibit the growth of NSPC cultures. Here, we further investigate its role as a candidate transcriptional regulator of neurogenic decline. We show that Dbx2 expression is downregulated by Epidermal Growth Factor receptor signaling, which promotes NSPC proliferation and decreases in the aged SVZ. By means of transgenic NSPC lines overexpressing Dbx2, we also show that this gene inhibits NSPC proliferation by hindering the G2/M transition. Furthermore, we exploit RNA sequencing of transgenic NSPCs to elucidate the transcriptomic networks modulated by Dbx2. Among the top hits, we report the downregulation of the molecular pathways implicated in cell cycle progression. Accordingly, we find that Dbx2 function is negatively correlated with the transcriptional signatures of proliferative NSPCs (aNSCs, TAPs and early NBs). These results point to Dbx2 as a transcription factor relaying the anti-neurogenic input of the aged niche to the NSPC transcriptome.Graphical

TIMP3 promotes the maintenance of neural stem-progenitor cells in the mouse subventricular zone.

Adult neural stem cells (NSCs) in the mouse subventricular zone (SVZ) serve as a lifelong reservoir for newborn olfactory bulb neurons. Recent studies have identified a slowly dividing subpopulation of embryonic neural stem-progenitor cells (NPCs) as the embryonic origin of adult NSCs. Yet, little is known about how these slowly dividing embryonic NPCs are maintained until adulthood while other NPCs are extinguished by the completion of brain development. The extracellular matrix (ECM) is an essential component of stem cell niches and thus a key determinant of stem cell fate. Here we investigated tissue inhibitors of metalloproteinases (TIMPs)-regulators of ECM remodeling-for their potential roles in the establishment of adult NSCs. We found that Timp2, Timp3, and Timp4 were expressed at high levels in slowly dividing NPCs compared to rapidly dividing NPCs. Deletion of TIMP3 reduced the number of adult NSCs and neuroblasts in the lateral SVZ. In addition, overexpression of TIMP3 in the embryonic NPCs suppressed neuronal differentiation and upregulated the expression levels of Notch signaling relating genes. These results thus suggest that TIMP3 keeps the undifferentiated state of embryonic NPCs, leading to the establishment and maintenance of adult NSCs.

Single-nucleus profiling of adult mice sub-ventricular zone after blast-related traumatic brain injury

Explosive blast-related traumatic brain injuries (bTBI) are common in war zones and urban terrorist attacks. These bTBIs often result in complex neuropathologic damage and neurologic complications. However, there is still a lack of specific strategies for diagnosing and/or treating bTBIs. The sub-ventricular zone (SVZ), which undergoes adult neurogenesis, is critical for the neurological maintenance and repair after brain injury. However, the cellular responses and mechanisms that trigger and modulate these activities in the pathophysiological processes following bTBI remain poorly understood. Here we employ single-nucleus RNA-sequencing (snRNA-seq) of the SVZ from mice subjected to a bTBI. This data-set, including 15272 cells (7778 bTBI and 7494 control) representing all SVZ cell types and is ideally suited for exploring the mechanisms underlying the pathogenesis of bTBIs. Additionally, it can serve as a reference for future studies regarding the diagnosis and treatment of bTBIs.

Developmental exposure to thyroid disruptors: misprogramming of the brain's stem cells in later life?

Developmental exposure to thyroid disruptors: misprogramming of the brain's stem cells in later life?

MiR-17∼92 exerts stage-specific effects in adult V-SVZ neural stem cell lineages.

Neural stem cells (NSCs) in the adult ventricular-subventricular zone (V-SVZ) generate neurons and glia throughout life. MicroRNAs are important post-transcriptional regulators frequently acting in a context-dependent manner. Here, microRNA profiling defines cohorts of miRNAs in quiescent and activated NSCs, with miR-17∼92 highly upregulated in activated NSCs and transit amplifying cells (TACs) versus quiescent NSCs. Conditional miR-17∼92 deletion in the adult V-SVZ results in stage-specific effects. In NSCs, it reduces proliferation invitro and invivo, whereas in TACs, it selectively shifts neurogenic OLIG2- DLX2+ toward oligodendrogenic OLIG2+ DLX2- TACs, due to de-repression of an oligodendrogenic program, leading to increased oligodendrogenesis invivo. This differential regulation of TAC subpopulations highlights the importance of TAC heterogeneity. Finally, in the NSC lineage for intraventricular oligodendrocyte progenitors, miR-17∼92 deletion decreases proliferation and maturation. Together, these findings reveal multiple stage-specific functions of the miR-17∼92 cluster within different adult V-SVZ lineages.

β-N-Methyl-Amino-L-Alanine cyanotoxin promotes modification of undifferentiated cells population and disrupts the inflammatory status in primary cultures of neural stem cells

β-N-Methyl-Amino-L-Alanine (BMAA) produced by 95% of cyanobacteria is in constant augmentation with cyanobacteria worldwide proliferation due to global warming and eutrophication. Previously, it has been shown that this contaminant induced neurological disorders, notably by acting as a developmental toxin. However, very few studies focus on the impact of BMAA on neuroglial cells, like astrocytes and microglial cells, in a developmental context. In the present study, we investigated whether BMAA disturbs neurogenesis from mice subventricular zone (SVZ) cells and whether this neurotoxin induces neuroinflammation. We show that BMAA at 100 µM disturbs the population of undifferentiated cells (B1 and C cells) and promotes their proliferation. Further, BMAA affects the organization of neuroblasts, indicating that SVZ function could be impaired. BMAA affects neuroinflammatory processes by increasing the release of proinflammatory cytokines IL-1β, IL-6 and TNFα. Our study adds to evidence that BMAA may disturb the central nervous system homeostasis by targeting glial cells. We highlighted that BMAA may impair SVZ niches and drives astrocytes and microglial cells into a proinflammatory status, with an ameboid shape for microglia.