RNA Sequencing of mouse Purkinje cells across postnatal development
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE86824 | GEO | 2019/01/31
REPOSITORIES: GEO
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Project description:Previous studies in bulk tissue suggest that there are abundant expression quantitative trait loci (eQTLs) in human brain. This sample series is of cerebellar Purkinje cells isolated using laser capture microdissection from human cases without neurological disease but of known genotypes. These data may be helpful in confirming eQTLs in bulk tissue or in mapping other gene expression traits in an enriched neuronal population. Authorized Access data: Mapping of GEO sample accessions to dbGaP subject/sample IDs is available through dbGaP Authorized Access, see http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000249 The aim of this study was to examine gene expression in isolated purkinje cells from the human cerebellum. We obtained frozen brain tissue from the cerebellum. We stained sections with cresyl violet and separated Purkinje cells based on morphology and location within the cerebellum using laser capture microdissection. Expression analyses were then performed.
2013-01-01 | E-GEOD-37205 | biostudies-arrayexpress
Project description:During the first 10 postnatal days of mouse development, Purkinje cells, neurons of the cerebellum, pass through different developmental processes of differentiation such as profound dendritic remodeling and growth, cell death and loss of their ability to regenerate their axons. To identify the genes involved in these different processes and in particular transcription factors, the gene expression patterns of murine cerebellar cortical area centered on Purkinje soma have been measured using Affymetrix microarrays at 5 different developmental stages (postnatal days P0, P3, P5, P7 and P10; 4 replicates = 4 independent measurements for each stage).
2012-03-15 | E-MEXP-3444 | biostudies-arrayexpress
Project description:The signalling protein PKCγ is a major regulator of Purkinje cell development and synaptic function. We have shown previously that increased PKCγ activity impairs dendritic development of cerebellar Purkinje cells. Mutations in the protein kinase Cγ gene (PRKCG) cause spinocerebellar ataxia type 14 (SCA14). In a transgenic mouse model of SCA14 expressing the human S361G mutation, Purkinje cell dendritic development is impaired in cerebellar slice cultures similar to pharmacological activation of PKC. The mechanisms of PKCγ-driven inhibition of dendritic growth are still unclear. Using immunoprecipitation-coupled mass spectrometry analysis we have identified Collapsin Response Mediator Protein 2 (CRMP2) as a protein interacting with constitutive active PKCγ(S361G) and confirmed the interaction with the Duolink™ proximity ligation assay. We show that in cerebellar slice cultures from PKCγ(S361G)- mice, phosphorylation of CRMP2 at the known PKC target site Thr555 is increased in Purkinje cells confirming phosphorylation of CRMP2 by PKCγ. miRNA-mediated CRMP2 knockdown decreased Purkinje cell dendritic outgrowth in dissociated cerebellar cultures as did the transfection of CRMP2 mutants with a modified Thr555 site. In contrast, dendritic development was normal after wildtype CRMP2 overexpression. In a novel knock-in mouse expressing only the phospho-defective T555A-mutant CRMP2, Purkinje cell dendritic development was reduced in dissociated cultures. This reduction could be rescued by transfecting wildtype CRMP2 but only partially by the phospho-mimetic T555D-mutant. Our findings establish CRMP2 as an important target of PKCγ phosphorylation in Purkinje cells mediating its control of dendritic development. Dynamic regulation of CRMP2 phosphorylation via PKCγ is required for its correct function.
2022-02-24 | PXD020124 | Pride
Project description:During cerebellar development, the main portion of the cerebellar plate neuroepithelium (NE) gives birth to Purkinje cells and interneurons, while the germinal zone at its dorsal edge, called the rhombic lip (RL), generates granule cells and cerebellar nuclei neurons. However, it remains elusive how these components work together to generate the intricate structure of the cerebellar anlage. In this study, we found that a polarized cerebellar anlage structure self-organizes in three-dimensional (3D) human ES cell (hESC) culture. This NE is capable of differentiating into electrophysiologically functional Purkinje cells. The addition of FGF19 promotes spontaneous generation of dorsoventrally polarized NE structures containing cerebellar and basal plates. Furthermore, further addition of SDF1 promoted the generation of stratified cerebellar plate NE with RL-like germinal zones self-forming at the edge. Thus, hESC-derived cerebellar progenitors exhibit substantial self-organizing potential for generating a polarized structure reminiscent of the early human cerebellar anlage at the first trimester. Examination of mRNA profile in two different treated human ES cells .
2015-04-15 | E-GEOD-63015 | biostudies-arrayexpress
Project description:We performed gene-expression analysis of mouse Purkinje cells as a model M-bM-^@M-^\single-type neuronM-bM-^@M-^]. DNA microarray analysis detected at least 7,055 genes in Purkinje cells, most of which are classified into functional molecule categories. Our comparative analysis between Purkinje cells and the granule cell layer showed that the characteristic expression pattern in Purkinje cells was particularly represented by M-bM-^@M-^\the neural communication systemM-bM-^@M-^] components. Pukinje cells and granule cell layer of the mouse cerebellum were collected by laser microdissection for RNA extraction and hybridization on Affymetrix microarrays.
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Project description:The assembly of neural circuits involves multiple sequential steps such as the specification of cell types, their migration to proper brain locations, morphological and physiological differentiation, and the formation and maturation of synaptic connections. This intricate and often prolonged process is guided by elaborate genetic mechanisms that regulate each developmental event. Evidence from numerous systems suggests that each cell type, once specified, is endowed with a genetic program that directs its subsequent development. This cell intrinsic program unfolds in respond to, and is regulated by, extrinsic signals, including cell-cell and synaptic interactions. To a large extent, the execution of this genetic program is achieved by the expression of specific sets of genes that support distinct developmental processes. Therefore, a comprehensive analysis of the developmental progression of gene expression in synaptic partners of neurons may provide a basis for exploring the genetic mechanisms regulating circuit assembly. Here we examined the developmental gene expression profiles in well defined cell types in a stereotyped microcircuit of the cerebellar cortex. Manually sorted pure populations of Purkinje cells and Stellate/Basket cells, 3 biological replicates, from Gad67-GFP bac-transgenic (G42) mice were profiled during postnatal developmental stages P3, P7, P14, P21, P28, P35 and P56 using Affymetrix MOE430.2 expression array
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Project description:The loss of Tmem106b results in an age-dependent loss of cerebellar Purkinje cells accompanied with motor function deficits. Tmem106b deficiency also results in lysosomal enlargement in both Purkinje cells and microglia, and increased neuroinflammation including complement system activation. These data suggest that, in addition to myelination, Tmem106b also plays important role in maintaining the health and survival of cerebellar Purkinje cells during aging.
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Project description:Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, the causal link between the activation of microglia in the cerebellum and ataxias remains inconclusive. In the present study, using a classic mouse model of cerebellar ataxia induced by 3-acetylpyridine (3-AP), we find a early-onset and long-lasting microglial activation accompanied by neuronal loss and dysfunction in the cerebellum. Transcriptome and behavior analyses indicate that microglial depletion in 3-AP ataxic mice decreases neuroinflammatory response in the cerebellum and rescues the ataxic motor symptoms including motor incoordination, gait abnormality, and locomotor dysfunction. Moreover, specific chemogenetic activation of cerebellar microglia in the vermis by M3D(Gq), a designer receptor exclusively activated by designer drugs (DREADDs), directly induces an expression of pro-inflammatory cytokines and aggravates ataxic motor deficits of 3-AP mice. On the contrary, inhibition of cerebellar microglial activation by M4D(Gi) or minocycline reduces the production of pro-inflammatory cytokines including TNF-α and alleviates motor deficits. Furthermore, blockage of TNF-α signaling attenuates the microglial-triggered hyperactivity of Purkinje cells (PCs). These results suggest that cerebellar microglial activation aggravates neuroinflammatory response, and subsequently induces dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between pro-inflammatory activation of cerebellar microglia and the ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.
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Project description:This SuperSeries is composed of the SubSeries listed below. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency. Refer to individual Series
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Project description:Identification of whole proteome changes in Purkinje cells of the cerebellum of AP-2 cKo and control mice at 2 months of age after APEX AAV injection
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