Targeting of mRNAs within the glial cell cytoplasm: How to hide the message along the journey

Boccaccio, Graciela Lidia

doi:10.1002/1097-4547(20001115)62:4<473::aid-jnr1>3.0.co;2-f

Cited by 7 publications

(6 citation statements)

References 63 publications

(78 reference statements)

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“…In addition, we observed similar patterns of DDR1 and MBP protein expression in human brain white matter (Roig et al 2010). The intracellular trafficking of RNA molecules implies that translation is inhibited during RNA transport and reactivated once the RNA arrives at its final destination (Boccaccio 2000;Kindler et al 2005). This process requires a regulatory mechanism that controls gene expression locally and prevents ectopic expression of the gene.…”

Section: Discussionmentioning

confidence: 57%

“…The intracellular trafficking of RNA molecules implies that translation is inhibited during RNA transport and reactivated once the RNA arrives at its final destination (Boccaccio 2000; Kindler et al. 2005).…”

Section: Discussionmentioning

confidence: 99%

“…The intracellular trafficking and the subsequent localized translation of mRNA molecules in subcellular compartments are important regulatory processes for gene expression. In the central nervous system, oligodendrocytes transport myelin components to their distal processes to form the myelin lamellae (Boccaccio 2000). In humans, myelin basic protein (MBP) is a major structural component of myelin.…”

mentioning

confidence: 99%

“…1996). Like MBP, other mRNAs, such as myelin‐associated oligodendrocytic basic protein (Boccaccio 2000), carboxyanhydrase II (Ghandour and Skoff 1991), microtubule‐associated protein tau (Barbarese et al. 1999) and amyloid precursor protein (Garcia‐Ladona et al.…”

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confidence: 99%

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The Discoidin domain receptor 1 gene has a functional A2RE sequence

Roig

Moyano

Martorell

et al. 2011

Journal of Neurochemistry

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J. Neurochem. (2012) 120, 408–418. Abstract Discoidin domain receptor 1 (DDR1) is expressed in myelin oligodendrocytes and co‐localizes with myelin basic protein (MBP). Alternative splicing of DDR1 generates five isoforms designated DDR1a–e. The MBP mRNA contains an hnRNP A2 response element (A2RE) sequence that is recognized by heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, which is responsible for transport of the MBP mRNA to oligodendrocyte processes. We hypothesized that DDR1 could have a functional A2RE sequence. By in silico analysis, we identified an A2RE‐like sequence in the human DDR1 mRNA. We observed nuclear and dendrite cytoplasmic immunofluorescence, indicating that DDR1 and hnRNP A2/B1 co‐localize in human oligodendrocytes and in differentiated HOG16 cells. The A2RE‐like sequence of DDR1 contains the single nucleotide polymorphism rs2267641, and we found that in the human brain, the minor allele is associated with lower and higher levels DDR1b and DDR1c mRNA expression, respectively. Moreover, a positive correlation between DDR1c and the myelin genes myelin‐associated glycoprotein and oligodendrocyte lineage transcription factor 2 was found. Differentiated HOG16 cells transfected with an hnRNP A2/B1 siRNA simultaneously show a decrease and an increase in the DDR1c and DDR1b mRNA expression levels, respectively, which was accompanied by a decrease in DDR1 protein levels at the cytoplasmic edges. These results suggest that the DDR1 A2RE sequence is functionally involved in the hnRNP A2/B1‐mediated splicing and transport of the DDR1c mRNA.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Discoidin domain receptor 1 gene has a functional A2RE sequence

Roig

Moyano

Martorell

et al. 2011

Journal of Neurochemistry

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“…This difference could reflect dependence by TECs on a nonphagosomal mechanism of antigen acquisition, such as peptide transfer via exosomes or gap junctions mediated by proximity of TECs to the cytosolic processes of myelinforming Schwann cells. Interestingly, MBP synthesis occurs within myelin membranes distal to the cell body because of translocation of MBP-encoding RNA from the nucleus to myelinating cytoplasmic processes (30). Translation is arrested while the RNA is transported, and the subsequent initiation of translation within the myelinating processes could result in localized production of classic MBP-derived defective ribosomal products (DRiPs) (31).…”

Section: Discussionmentioning

confidence: 99%

Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein

Perchellet¹,

Brabb

Goverman³

2008

Proc. Natl. Acad. Sci. U.S.A.

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Central tolerance plays a critical role in eliminating self-reactive T cells specific for peripheral antigens. Here we show that central tolerance of MHC class I-restricted T cells specific for classic myelin basic protein (MBP), a component of the myelin sheath, is mediated by both bone marrow (BM)-derived and nonBM-derived cells. Unexpectedly, BM-derived cells induce tolerance directly by using classic MBP that they synthesize, whereas nonBM-derived cells mediate tolerance by crosspresenting classic MBP acquired from an exogenous source. Thus, tolerance to tissue-specific antigens can involve multiple cell types and mechanisms in the thymus, which may account for the limited spectrum of autoimmune syndromes observed when expression of tissue-specific antigens is impaired only in thymic epithelial cells.autoimmunity ͉ EAE ͉ multiple sclerosis D efining the mechanisms that maintain tolerance to tissuespecific antigens (TSAs) is critical for understanding the pathogenesis of organ-specific autoimmune diseases such as multiple sclerosis (MS). Tolerance of many TSAs occurs in the thymus and is facilitated by medullary thymic epithelial cells (mTECs) that promiscuously express a broad range of TSAs (1). TSAs synthesized and presented by mTECs can induce tolerance in the MHC class I and II pathways (2, 3). In addition, bone marrow (BM)-derived cells can acquire TSAs from mTECs and induce both CD4 ϩ and CD8 ϩ T cell tolerance (2, 4). However, in vivo studies indicate that, under physiological conditions, only BM-derived cells acquire sufficient TSA from exogenous sources to negatively select MHC class II-restricted T cells (3,5).We investigated the mechanisms that induce central tolerance to myelin basic protein (MBP), which is believed to be targeted by self-reactive T cells in MS. The genetic organization of the MBP locus may influence how tolerance is induced to this self-antigen. The MBP locus encodes two separate protein families that are transcribed by using different promoters, both of which generate multiple isoforms via alternative splicing (6). One family consists of MBP isoforms that are incorporated into myelin (classic MBP) and are considered TSAs because of their restricted expression in myelin-forming cells. Proteins in the other family (golli MBP) modulate calcium influx (7,8) and are expressed in the nervous system, thymus, and peripheral lymphoid tissues (6). Although the two families differ functionally, classic and golli MBP are immunologically related because they contain stretches of identical amino acid sequence because of exon sharing (6). Thus, expression of golli MBP in the thymus could mediate negative selection of many classic MBP-specific T cells.We sought to define tolerance mechanisms for CD4 ϩ and CD8 ϩ MBP-specific T cells because both subsets mediate autoimmunity (5, 9, 10). We previously found that CD4 ϩ MHC class II-restricted T cells specific for MBP121-140, an epitope present in classic but not golli MBP, undergo central tolerance mediated by BM-derived cells that acquire classic ...

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Developmental changes of tau protein and mRNA in cultured rat brain oligodendrocytes

Gorath¹,

Stahnke²,

Mronga³

et al. 2001

Glia

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Oligodendrocytes elaborate an extensive network of multibranched processes and flat membranous sheets. Microtubules (MT) participate in the elaboration and stabilization of myelin-forming processes and are essential for cellular sorting processes. Microtubule-associated proteins (MAPs) are involved in the regulation and stabilization of the dynamic MT network. It has been shown previously that oligodendrocytes express the MAP tau, a phosphoprotein most abundant in neurons of the CNS. In this article, we demonstrate for the first time that oligodendrocytes contain all six tau isoforms, and that tau mRNA and protein expression is developmentally regulated. Immunoblot analysis reveals that tau protein is more abundant, and mature isoforms are more prominent at later stages of development. During the first week of culture maturation, a marked decrease in phosphorylation is observable. Using an RT-PCR approach, we can show that oligodendrocytes express small amounts of exon 3 containing isoforms and that during culture maturation, tau mRNA splice products with 3 MT-binding domains (3R) decrease and mRNA with 4 MT-binding domains (4R) increase. In situ hybridization study demonstrates that tau mRNA is present in precursor cells and in mature oligodendrocytes. Tau mRNA is actively transported into the cellular processes, is specifically present in the primary and some of the secondary processes, enriched at the turning and branching points and the growing tips, and often appears as small patches. Hence, localized tau translation at specific sites in the cellular extensions might contribute to the regulation of MT stability during process formation, early axonal contact establishment, and myelination.

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Targeting of mRNAs within the glial cell cytoplasm: How to hide the message along the journey

Cited by 7 publications

References 63 publications

The Discoidin domain receptor 1 gene has a functional A2RE sequence

The Discoidin domain receptor 1 gene has a functional A2RE sequence

Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein

Developmental changes of tau protein and mRNA in cultured rat brain oligodendrocytes

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