An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex

Zhang, Ye; Chen, Kenian; Sloan, Steven A.; Bennett, Mariko L.; Scholze, Anja R.; O’Keeffe, Sean; Phatnani, Hemali; Guarnieri, Paolo; Caneda, Christine; Ruderisch, Nadine; Deng, S.Z.; Liddelow, Shane A.; Zhang, Chaolin; Daneman, Richard; Maniatis, Tom; Barres, Ben A.; Wu, Jian

doi:10.1523/jneurosci.1860-14.2014

Cited by 4,380 publications

(5,795 citation statements)

References 91 publications

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“…3B; see also Cahoy et al, 2008; Zhang et al, 2014). Notably, reactive astrocytes showed significantly lower expression of most astrocyte‐specific genes (selected as astrocyte‐specific from Cahoy et al 2008, Zhang et al 2014), except for Aldh1l1 and GFAP (Fig. 3B).…”

Section: Resultsmentioning

confidence: 89%

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

Sirko

Irmler

Gascón

et al. 2015

Glia

116

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Astrocytes react to brain injury in a heterogeneous manner with only a subset resuming proliferation and acquiring stem cell properties in vitro. In order to identify novel regulators of this subset, we performed genomewide expression analysis of reactive astrocytes isolated 5 days after stab wound injury from the gray matter of adult mouse cerebral cortex. The expression pattern was compared with astrocytes from intact cortex and adult neural stem cells (NSCs) isolated from the subependymal zone (SEZ). These comparisons revealed a set of genes expressed at higher levels in both endogenous NSCs and reactive astrocytes, including two lectins—Galectins 1 and 3. These results and the pattern of Galectin expression in the lesioned brain led us to examine the functional significance of these lectins in brains of mice lacking Galectins 1 and 3. Following stab wound injury, astrocyte reactivity including glial fibrillary acidic protein expression, proliferation and neurosphere‐forming capacity were found significantly reduced in mutant animals. This phenotype could be recapitulated in vitro and was fully rescued by addition of Galectin 3, but not of Galectin 1. Thus, Galectins 1 and 3 play key roles in regulating the proliferative and NSC potential of a subset of reactive astrocytes. GLIA 2015;63:2340–2361

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Section: Resultsmentioning

confidence: 89%

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

Sirko

Irmler

Gascón

et al. 2015

Glia

116

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“… a , Nlgn3 RNA expression (FPKM values) in various cell types; (data from Brain-seq Barres dataset 13 ) b-c , Recombination rate of inducible Cre driver models 7 days after treatment with tamoxifen (100mg/kg for 5 days) in Rosa26 ::tdTomato lox-stop-lox reporter mice. b , To assess the neuron-specific CamKIIa :Cre ER Cre driver, recombination efficiency was quantified as percent of NeuN+ neurons that co-express tdTomato+ in the cortex of either CamKIIa :Cre ER − or CamKIIa :Cre ER + mice 7 days following completion of tamoxifen administration.…”

Section: Extended Datamentioning

confidence: 99%

“…Neuroligin-3 is highly expressed in both neurons and in oligodendrocyte precursor cells 13 (OPCs; Extended Data Fig. 4a), known to form bona fide synapses with presynaptic neurons and serve as a post-synaptic cell 14–16 .…”

mentioning

confidence: 99%

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Venkatesh

Tam

Woo

et al. 2017

Nature

402

374

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Summary High-grade gliomas (HGG) are a devastating group of cancers, representing the leading cause of brain tumor-related death in both children and adults. Therapies aimed at mechanisms intrinsic to the glioma cell have translated to only limited success; effective therapeutic strategies will need to also target elements of the tumor microenvironment that promote glioma progression. We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG)1. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway1. However, neuroligin-3 necessity to glioma growth, proteolytic mechanism of secretion and further molecular consequences in glioma remain to be clarified. Here, we demonstrate a striking dependence of HGG growth on microenvironmental neuroligin-3, elucidate signaling cascades downstream of neuroligin-3 binding in glioma and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. Neuroligin-3 stimulates numerous oncogenic pathways, including early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes including upregulation of numerous synapse-related genes in glioma cells. Neuroligin-3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent release of neuroligin-3 into the tumor microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting neuroligin-3 secretion, which could prove transformative for HGG therapy.

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“…In contrast to the mixed distribution of GPR37, GPR37L1 is highly expressed in astrocytes, with in situ hybridization revealing greatest density of GPR37L1 within the Bergmann glia of the cerebellum (Valdenaire et al, 1998). Microarray studies reported more than 100 times higher expression of GPR37L1 in rat and mice astrocytes compared with neurons (Cahoy et al, 2008; Lovatt et al, 2007; Zhang et al, 2014). GPR37L1 is also expressed in oligodendrocytes (Zhang et al, 2014).…”

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

“…Microarray studies reported more than 100 times higher expression of GPR37L1 in rat and mice astrocytes compared with neurons (Cahoy et al, 2008; Lovatt et al, 2007; Zhang et al, 2014). GPR37L1 is also expressed in oligodendrocytes (Zhang et al, 2014). These results are consistent with our own, yet unpublished, transcriptomic analysis of rat brainstem astrocytes.…”

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex

Cited by 4,380 publications

References 91 publications

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

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