Gene expression profile at single nuclei level of cerebellar neurons (Purkinje cells) and glia (Bergmann glia, velate astrocytes and oligodendrocytes) in a transenic mouse model of Spinocerebellar Ataxia Type 1 (SCA1)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE215336 | GEO | 2022/12/05
REPOSITORIES: GEO
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Project description:Recent studies have shown that cerebellar Bergmann glia display coordinated Ca(2+) transients in live mice. However, the functional significance of Bergmann glial Ca(2+) signaling remains poorly understood. Using transgenic mice that allow selective stimulation of glial cells, we report here that cytosolic Ca(2+) regulates uptake of K(+) by Bergmann glia, thus providing a powerful mechanism for control of Purkinje cell-membrane potential. The decline in extracellular K(+) evoked by agonist-induced Ca(2+) in Bergmann glia transiently increased spike activity of Purkinje cells in cerebellar slices as well as in live anesthetized mice. Thus, Bergmann glia play a previously unappreciated role in controlling the membrane potential and thereby the activity of adjacent Purkinje cells.
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Project description:For decades, the glial function has been highlighted not only as the 'structural glue', but also as an 'active participant' in neural circuits. Here, we suggest that tumor necrosis factor ? (TNF-?), a key inflammatory cytokine, alters the neural activity of the cerebellar Purkinje cells (PCs) by facilitating gliotransmission in the juvenile male rat cerebellum. A bath application of TNF-? (100?ng/ml) in acute cerebellar slices elevates spiking activity of PCs with no alterations in the regularity of PC firings. Interestingly, the effect of TNF-? on the intrinsic excitability of PCs was abolished under a condition in which the type1 TNF receptor (TNFR1) in Bergmann glia (BG) was genetically suppressed by viral delivery of an adeno-associated virus (AAV) containing TNFR1-shRNA. In addition, we measured the concentration of glutamate derived from dissociated cerebellar cortical astrocyte cultures treated with TNF-? and observed a progressive increase of glutamate in a time-dependent manner. We hypothesised that TNF-?-induced elevation of glutamate from BGs enveloping the synaptic cleft may directly activate metabotropic glutamate receptor1 (mGluR1). Pharmacological inhibition of mGluR1, indeed, prevented the TNF-?-mediated elevation of the intrinsic excitability in PCs. Taken together, our study reveals that TNF-? triggers glutamate release in BG, thereby increasing the intrinsic excitability of cerebellar PCs in a mGluR1-dependent manner.
| S-EPMC6072779 | biostudies-literature
Project description:Ataxin 1 (Atxn1) is a protein of unknown function associated with cerebellar neurodegeneration in spinocerebellar ataxia type 1 (SCA1). SCA1 is caused by an expanded polyglutamine within Atxn1 by gain-of-function mechanisms. Lack of Atxn1 in mice triggers motor deficits in the absence of neurodegeneration or apparent neuropathological abnormalities.We extracted RNA from cerebellum of 5 Atxn1-null mice and 5 WT. Cerebellar gene expression profiles at 15 weeks of age were generated usSCA1 ing Affymetrix MOE430A arrays. Identifying the molecular pathways regulated by Atxn1 can provide insights into the early molecular mechanisms underlying neuronal dysfunction.
2006-12-01 | E-MEXP-886 | biostudies-arrayexpress
Project description:Neocortical basal radial glia (bRG) and cerebellar Bergmann glia (BG) are basal progenitors derived from ventricular apical radial glia (aRG) that selectively lose their apical processes. bRG and BG have been implicated in the expansion and folding of the cerebrum and cerebellum, respectively. Here, we analyzed the molecular characteristics and development of bRG and BG. Transcriptomic comparison revealed striking similarity of the molecular features of bRG and BG. We found that heightened ERK signaling activity in aRG is tightly linked to the temporal formation and the relative abundance of bRG in human and mouse cortices. Forced activation of an FGF-ERK-ETV axis that is crucial to BG induction specifically induced bRG with canonical human bRG features in mice. Therefore, our data point to a common mechanism of bRG and BG generation, bearing implications to the role for these basal progenitors in the evolution of cortical folding of the cerebrum and cerebellum.
| S-EPMC5457141 | biostudies-literature
Project description:Cortical lamination is crucial for the assembly of cerebellar circuitry. In this process, granule neurons (GNs) migrate along Bergmann glia (BG), which are specialized astroglial cells, from the external granule layer to the internal granule layer. However, the molecular mechanisms underlying BG development are not well understood. Here, we show that GFAP::Cre;Erbb3(F/F) mice, which lack Erbb3 in both radial glia and neurons, exhibit impairments in balance and motor coordination. Cerebellar lamination is aberrant, with misplaced Purkinje neurons and GN clusters. These phenotypes were not observed in Math1::CreER(T2);Erbb3(F/F) mice, where the Erbb3 gene was deleted in GNs, suggesting involvement of non-neuronal Erbb3 in cerebellar lamination. Mechanistic studies indicate that ERBB3 is crucial for the proliferation of BG, which are required for GN migration. These observations identify a crucial role for ERBB3 in cerebellar lamination and reveal a novel mechanism that regulates BG development.
| S-EPMC4302995 | biostudies-literature
Project description:Spinocerebellar ataxia type 1 (SCA1) is caused by a polyglutamine expansion in the ATXN1 gene leading to an expanded polyglutamine tract in the ATAXIN-1 protein. Ataxin-1 is broadly expressed throughout the brain and is known to be involved in regulating gene expression; however, it is not yet determined if mutant ataxin-1 regulates alternative splicing events. Utilizing SCA1 mouse models, we performed bulk RNA sequencing and looked for misregulated alternative splicing (mAS) events in SCA1 mouse cerebella. We found that mutant ataxin-1 causes mAS events to occur in the SCA1 mouse cerebella. Furthermore, we showed that abnormal splicing events predominantly occur in cell types that express mutant ataxin-1. Less than 25% of the mAS events were also differentially expressed genes (DEGs) and therefore their transcriptional dysregulation was previously unknown in the context of SCA1. We show through gene ontology analysis that mAS events reveal new biological pathways: mAS events showed changes in structural morphogenesis whereas DEGs showed changes in ion channel and transmembrane transport. We also report that mutant ataxin-1 causes dysregulation of expression of other ataxia-causing genes, providing evidence for molecular basis of clinical similarity among otherwise heterogeneous inherited cerebellar ataxias. We also identified the potential mechanism by which mutant ATXN1 causes mAS through its interaction with RBFOX1.
2023-10-20 | GSE232368 | GEO
Project description:Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which a primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion of ataxin-1 protein (ATXN1), phosphorylation of ATXN1 at the serine 776 residue (ATXN1-pS776) plays a significant role in protein toxicity. Utilizing a biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine the role of Protein Kinase A (PKA) as an effector of ATXN1-S776 phosphorylation. We further examine the implications of PKA-mediated phosphorylation at ATXN1-S776 on SCA1 through genetic manipulation of the PKA catalytic subunit Cα in Pcp2-ATXN1[82Q] mice. Here we show that pharmacologic inhibition of S776 phosphorylation in transfected cells and SCA1 patient iPSC-derived neuronal cells lead to a decrease in ATXN1. In vivo, reduction of PKA-mediated ATXN1-pS776 results in enhanced degradation of ATXN1 and improved cerebellar-dependent motor performance. These results provide evidence that PKA is a biologically important kinase for ATXN1-pS776 in cerebellar Purkinje cells.
2019-05-31 | GSE114815 | GEO
Project description:Bergmann glia (BG) are important in the inward type of radial migration of cerebellar granule neurons (CGNs). However, details regarding the functions of Cdc42 and Rac in BG for radial migration of CGN are unknown. To examine the roles of Cdc42 and Rac in BG during cerebellar corticogenesis, mice with a single deletion of Cdc42 or Rac1 and those with double deletions of Cdc42 and Rac1 under control of the glial fibrillary acidic protein (GFAP) promoter: GFAP-Cre;Cdc42flox/flox (Cdc42-KO), GFAP–Cre;Rac1flox/flox (Rac1-KO), and GFAP-Cre;Cdc42 flox/flox;Rac1flox/flox (Cdc42/Rac1-DKO) mice, were generated. Both Cdc42-KO and Rac1-KO mice, but more obviously Cdc42-KO mice, had disturbed alignment of BG in the Purkinje cell layer (PCL). We found that Cdc42-KO, but not Rac1-KO, induced impaired radial migration of CGNs in the late phase of radial migration, leading to retention of CGNs in the inferior half of the molecular layer (ML). Cdc42-KO, but not Rac1-KO, mice also showed aberrantly aligned Purkinje cells (PCs). These phenotypes were exacerbated in Cdc42/Rac1-DKO mice. Alignment of BG radial fibers in the ML and BG endfeet at the pial surface of the cerebellum evaluated by GFAP staining was disturbed and weak in Cdc42/Rac1-DKO mice, respectively. Our data indicate that that Cdc42 and Rac, but predominantly Cdc42, in BG play important roles during the late phase of radial migration of CGNs. We also report here that Cdc42 is involved in gliophilic migration of CGNs, in contrast to Rac, which is more closely connected to regulating neurophilic migration.
2018-01-01 | GSE106141 | GEO
Project description:Cerebellar circuitry is critical for balance and motor control among a wide array of functions and largely consists of granule and Purkinje neurons. Bergmann glia in the cerebellum form distinct morphological structures that facilitate granule neuron migration during development and that maintain the cerebellar organization and functional integrity. At present, molecular control of the formation and morphogenesis of Bergmann glia remains obscure. In this study, we found that Zeb2 (a.k.a. Sip1 or Zfhx1b), a Mowat-Wilson syndrome-associated transcriptional regulator, is highly restricted to Bergmann glia and is essential for their development and maturation. The mice with Zeb2 ablation in the cerebellar neural progenitor exhibit dysgenesis of cerebellar cortical lamination and locomotion defects. Deletion of Zeb2 markedly reduced Bergmann glial proliferation, differentiation and the establishment of the normal radial scaffold, disrupting migration of granule cell progenitors from external to internal granular layers. Transcriptome profiling indicated that Zeb2 regulates multiple pathways including FGF and Notch signaling as well as axonal guidance cues including Netrin G2 and Gdf10 to control Bergmann glial development. Our data reveal that Zeb2 acts as a transcriptional integrator of diverse signaling pathways to regulate the formation and morphogenesis of Bergmann glia ensuring maintenance of cerebellar integrity, suggesting that Zeb2 dysfunction in Bergmann glia might contribute to motor deficits in Mowat-Wilson syndrome.
2018-06-25 | GSE84098 | GEO
Project description:Purpose: The goals of this study were to identify the molecular alterations in the SCA1 inferior olive, and determine whether these changes are found in other affected tissues. Methods: mRNA profiling was conducted in two different SCA1 mouse models (Atxn1 154Q/2Q KI and ATXN1-82Q Tg), in two different affected tisues (inferior olive and cerebellum) during early disease initiation and progression (5 week and 12 week time-points). All analyses were conducted relative to appropriate wild-type controls. TopHat2 v2.1.0 was utilized to align reads to the mouse reference genome (mm10) before quantification and differential expression analysis with Cufflinks v2.2.1. Normalized expression values were generated using Cuffnorm. Results: Differentially regulated genes identified in the SCA1 inferior olive segregated into several enriched biological pathways, including the Defense Response at 12 weeks of age. Our study demonstrates that vulnerable tissues in SCA1 are not uniform in their gene expression changes, and express discrete and commonly enriched biological pathways. In addition, we found that brain region-specific differences occur early in disease initiation and progression at 5 weeks of age. Conclusions: The findings from this study suggest that different mechanisms of neurodegeneration are at work in the SCA1 inferior olive and cerebellum.
2018-12-04 | GSE122099 | GEO