Neuron–glia signaling: Implications for astrocyte differentiation and synapse formation

Stipursky, Joice; Romão, Luciana; Tortelli, Vanessa; Neto, Vivaldo Moura; Gomes, Flávia Carvalho Alcântara

doi:10.1016/j.lfs.2011.04.005

Cited by 44 publications

(28 citation statements)

References 134 publications

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“…In several neuronal cell models, including hippocampal cultures, the presence of astrocytes improves and speeds up neuronal differentiation [21], [22]. We asked therefore if the presence of astrocytes could modify CNF1 effects on neuronal cell growth.…”

Section: Resultsmentioning

confidence: 99%

CNF1 Improves Astrocytic Ability to Support Neuronal Growth and Differentiation In vitro

et al. 2012

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Modulation of cerebral Rho GTPases activity in mice brain by intracerebral administration of Cytotoxic Necrotizing Factor 1 (CNF1) leads to enhanced neurotransmission and synaptic plasticity and improves learning and memory. To gain more insight into the interactions between CNF1 and neuronal cells, we used primary neuronal and astrocytic cultures from rat embryonic brain to study CNF1 effects on neuronal differentiation, focusing on dendritic tree growth and synapse formation, which are strictly modulated by Rho GTPases. CNF1 profoundly remodeled the cytoskeleton of hippocampal and cortical neurons, which showed philopodia-like, actin-positive projections, thickened and poorly branched dendrites, and a decrease in synapse number. CNF1 removal, however, restored dendritic tree development and synapse formation, suggesting that the toxin can reversibly block neuronal differentiation. On differentiated neurons, CNF1 had a similar effacing effect on synapses. Therefore, a direct interaction with CNF1 is apparently deleterious for neurons. Since astrocytes play a pivotal role in neuronal differentiation and synaptic regulation, we wondered if the beneficial in vivo effect could be mediated by astrocytes. Primary astrocytes from embryonic cortex were treated with CNF1 for 48 hours and used as a substrate for growing hippocampal neurons. Such neurons showed an increased development of neurites, in respect to age-matched controls, with a wider dendritic tree and a richer content in synapses. In CNF1-exposed astrocytes, the production of interleukin 1β, known to reduce dendrite development and complexity in neuronal cultures, was decreased. These results demonstrate that astrocytes, under the influence of CNF1, increase their supporting activity on neuronal growth and differentiation, possibly related to the diminished levels of interleukin 1β. These observations suggest that the enhanced synaptic plasticity and improved learning and memory described in CNF1-injected mice are probably mediated by astrocytes.

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Section: Resultsmentioning

confidence: 99%

CNF1 Improves Astrocytic Ability to Support Neuronal Growth and Differentiation In vitro

et al. 2012

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“…The role of the Jak-Stat signaling pathway in the brain, however, is unclear. Jak-Stat signaling has recently been implicated in neurogenesis/cell-fate determination [59, 60], astrogliogenesis [61, 62] and synaptic plasticity [63, 64] within the nervous system of rats and fruit flies, but not specifically in the development and progression of neuropathology in mouse models or individuals with DS. Elevation of STAT1 activities has been shown to promote astrogliogenesis during the neurogenic phase of development [61].…”

Section: Discussionmentioning

confidence: 99%

Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks

et al. 2014

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BackgroundThe Ts1Cje mouse model of Down syndrome (DS) has partial triplication of mouse chromosome 16 (MMU16), which is partially homologous to human chromosome 21. These mice develop various neuropathological features identified in DS individuals. We analysed the effect of partial triplication of the MMU16 segment on global gene expression in the cerebral cortex, cerebellum and hippocampus of Ts1Cje mice at 4 time-points: postnatal day (P)1, P15, P30 and P84.ResultsGene expression profiling identified a total of 317 differentially expressed genes (DEGs), selected from various spatiotemporal comparisons, between Ts1Cje and disomic mice. A total of 201 DEGs were identified from the cerebellum, 129 from the hippocampus and 40 from the cerebral cortex. Of these, only 18 DEGs were identified as common to all three brain regions and 15 were located in the triplicated segment. We validated 8 selected DEGs from the cerebral cortex (Brwd1, Donson, Erdr1, Ifnar1, Itgb8, Itsn1, Mrps6 and Tmem50b), 18 DEGs from the cerebellum (Atp5o, Brwd1, Donson, Dopey2, Erdr1, Hmgn1, Ifnar1, Ifnar2, Ifngr2, Itgb8, Itsn1, Mrps6, Paxbp1, Son, Stat1, Tbata, Tmem50b and Wrb) and 11 DEGs from the hippocampus (Atp5o, Brwd1, Cbr1, Donson, Erdr1, Itgb8, Itsn1, Morc3, Son, Tmem50b and Wrb). Functional clustering analysis of the 317 DEGs identified interferon-related signal transduction as the most significantly dysregulated pathway in Ts1Cje postnatal brain development. RT-qPCR and western blotting analysis showed both Ifnar1 and Stat1 were over-expressed in P84 Ts1Cje cerebral cortex and cerebellum as compared to wild type littermates.ConclusionsThese findings suggest over-expression of interferon receptor may lead to over-stimulation of Jak-Stat signaling pathway which may contribute to the neuropathology in Ts1Cje or DS brain. The role of interferon mediated activation or inhibition of signal transduction including Jak-Stat signaling pathway has been well characterized in various biological processes and disease models including DS but information pertaining to the role of this pathway in the development and function of the Ts1Cje or DS brain remains scarce and warrants further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-624) contains supplementary material, which is available to authorized users.

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“…Radial glia maintenance and/or differentiation results from a balance between neurogenic and stem cell-maintaining molecules such as neuregulin-1 and Notch1 [14,15,16,17,73,74,75,76,77,78,79], and differentiating molecules such as TGF-β 1 [26,80], cardiotrophin [25] and ciliary neurotrophic factor [18], which are crucial to control the correct timing of the neurogenic-to-gliogenic switch of radial glia cells. …”

Section: Discussionmentioning

confidence: 99%

“…Radial glia cells are originated from the neuroepithelial cells of the neural tube, and although they retain a morphology and intermediate filament nestin expression similar to the neuroepithelial cells, some of the features that define the neuroepithelial-radial glia transition are the expression of genes that are related to the astrocytic lineage, such as the brain lipid-binding protein (BLBP), the astrocytic glutamate-aspartate transporter (GLAST), the adhesion molecule tenascin-C, the enzyme glutamine synthase, the calcium-binding protein S100β and the intermediate filament vimentin [3,4]. In early cerebral cortex development, radial glia cells divide in the ventricular zone and give rise to neurons that migrate along their radial fibers toward the pial surface to form the specific cortical layers, and by the end of the neuronal migratory period, radial glia cells transform into astrocytes [2,3,4,5,6,7,8,9,10,11,12,13,14,15]. …”

Section: Introductionmentioning

confidence: 99%

Activation of MAPK/PI3K/SMAD Pathways by TGF-β1 Controls Differentiation of Radial Glia into Astrocytes in vitro

Stipursky

Francis

Gomes³

2012

Dev Neurosci

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The major neural stem cell population in the developing cerebral cortex is the radial glia cells, which generate neurons and glial cells. The mechanisms that modulate the maintenance of the radial glia stem cell phenotype, or its differentiation, are not completely elucidated. We previously demonstrated that transforming growth factor-β₁ (TGF-β₁) promotes radial glia differentiation into astrocytes in vitro [Glia 2007;55:1023–1033]. Here we investigated the intracellular signaling pathways involved in the TGF-β₁-induced radial glia fate commitment. We demonstrate that the mechanisms underlying the TGF-β₁ effect on radial glia cell differentiation or progenitor potential maintenance diverge. Whereas radial glia differentiation into astrocytes is mediated by the activation of the MAPK signaling pathway, neurogenesis is modulated by different levels of PI3K and SMAD2/3 activity. Our work demonstrates that radial glia cells are a heterogeneous population and a potential target of TGF-β₁, and suggests that its effect on radial glia fate commitment is mediated by the recruitment of a complex multipathway mechanism that controls astrocyte and neuronal generation in the developing cerebral cortex.

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Neuron–glia signaling: Implications for astrocyte differentiation and synapse formation

Cited by 44 publications

References 134 publications

CNF1 Improves Astrocytic Ability to Support Neuronal Growth and Differentiation In vitro

CNF1 Improves Astrocytic Ability to Support Neuronal Growth and Differentiation In vitro

Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks

Activation of MAPK/PI3K/SMAD Pathways by TGF-β1 Controls Differentiation of Radial Glia into Astrocytes in vitro

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