Neuronal cell type–specific alternative splicing is regulated by the KH domain protein SLM1

Iijima, Takahiro; Iijima, Yoko; Witte, Harald; Scheiffele, Peter

doi:10.1083/jcb.201310136

Cited by 84 publications

(116 citation statements)

References 47 publications

(71 reference statements)

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“…KHDRBS2 is an RNA-binding protein thought to regulate alternative splicing (Iijima et al 2014). To investigate the ability of intronic tumor-specific L1 insertions to influence gene expression, we performed qRT-PCR using RNA extracted from tumor and nontumor liver tissue from the patient bearing the KHDRBS2 L1 insertion (HCC.58) and nine other HCC tumor/nontumor tissue pairs.…”

Section: Resultsmentioning

confidence: 99%

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

et al. 2018

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The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) is a continuing source of germline and somatic mutagenesis in mammals. Deregulated L1 activity is a hallmark of cancer, and L1 mutagenesis has been described in numerous human malignancies. We previously employed retrotransposon capture sequencing (RC-seq) to analyze hepatocellular carcinoma (HCC) samples from patients infected with hepatitis B or hepatitis C virus and identified L1 variants responsible for activating oncogenic pathways. Here, we have applied RC-seq and whole-genome sequencing (WGS) to an Abcb4 (Mdr2)−/− mouse model of hepatic carcinogenesis and demonstrated for the first time that L1 mobilization occurs in murine tumors. In 12 HCC nodules obtained from 10 animals, we validated four somatic L1 insertions by PCR and capillary sequencing, including T F subfamily elements, and one G F subfamily example. One of the T F insertions carried a 3 ′ transduction, allowing us to identify its donor L1 and to demonstrate that this full-length T F element retained retrotransposition capacity in cultured cancer cells. Using RC-seq, we also identified eight tumor-specific L1 insertions from 25 HCC patients with a history of alcohol abuse. Finally, we used RC-seq and WGS to identify three tumor-specific L1 insertions among 10 intra-hepatic cholangiocarcinoma (ICC) patients, including one insertion traced to a donor L1 on Chromosome 22 known to be highly active in other cancers. This study reveals L1 mobilization as a common feature of hepatocarcinogenesis in mammals, demonstrating that the phenomenon is not restricted to human viral HCC etiologies and is encountered in murine liver tumors.

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Section: Resultsmentioning

confidence: 99%

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

et al. 2018

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“…The depolarization-dependent alternative splicing shift at NRXN1 and NRXN3 SS4 was impaired in SAM68 -/-neurons compared with a significant upregulation of the NRXN1 SS4 splice variant in (SAM68 +/-) neurons (Iijima et al, 2011). However, SAM68 did not exhibit significant activity toward NRXN2 (SS4), whereas SLM1 and SLM2 induced exon skipping in NRXN2 (Iijima et al, 2014). SLM1 and SLM2 are expressed in largely segregated neuronal populations.…”

Section: Rna Binding Proteinsmentioning

confidence: 89%

“…For example, in the cerebellum, SLM1 is highly concentrated in Purkinje cells, whereas SLM2 marks interneurons in the inner granular and molecular layer. Thus, SLM1 and SLM2 are restricted to subpopulations of neurons in the brain (Iijima et al, 2014). Distribution of SLM1 and SLM2 proteins in vivo is strikingly non-overlapping.…”

Section: Rna Binding Proteinsmentioning

confidence: 96%

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Regulation and postsynaptic binding of neurexins — drug targets for neurodevelopmental and neuropsychiatric disorders

et al. 2015

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Neurexins (NRXNs) have been linked to neurodevelopmental and neuropsychiatric disorders and have become attractive drug targets. They are transmembrane neuronal adhesion molecules and play important roles in the formation and differentiation of synapses and synaptic activity. Many postsynaptic binding partners of NRXNs have been identified. The interactions between NRXNs and postsynaptic binding partners can be regulated by alternative splicing, synaptic activity, and RNA binding proteins. The postsynaptic interactive partners may compete with each other for NRXN binding. The expression of NRXNs can also be regulated transcriptionally and post-transcriptionally. Genetic polymorphism may affect the function and expression of NRXNs. In this review, we will summarize the recent advance in these areas. Understanding the biology of neurexin signaling is essential for developing neurexin-based drugs.

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“…In addition, Sam68 is involved in the nuclear export of the unspliced HIV (human immunodeficiency virus) RNA through binding directly the viral Rev protein and the viral RNA [26]. While Sam68 is ubiquitously expressed in all tissues, SLM1 and SLM2/T-STAR exhibit preferential expression in the brain where they specifically act as alternative splicing regulators of the Neurexin 1-3 genes [27,28]. QKI is involved in the regulation of alternative splicing, RNA export, and mRNA stability of myelin-associated premRNAs [29,30].…”

Section: Function Of Star Proteins In Rna Metabolismmentioning

confidence: 99%

Structural investigations of the RNA-binding properties of STAR proteins

Feracci

Foot

Dominguez

2014

Biochemical Society Transactions

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STAR (signal transduction and activation of RNA) proteins are a family of RNA-binding proteins that regulate post-transcriptional gene regulation events at various levels, such as pre-mRNA alternative splicing, RNA export, translation and stability. Most of these proteins are regulated by signalling pathways through post-translational modifications, such as phosphorylation and arginine methylation. These proteins share a highly conserved RNA-binding domain, denoted STAR domain. Structural investigations of this STAR domain in complex with RNA have highlighted how a subset of STAR proteins specifically recognizes its RNA targets. The present review focuses on the structural basis of RNA recognition by this family of proteins.

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Neuronal cell type–specific alternative splicing is regulated by the KH domain protein SLM1

Abstract: Cell type–specific expression of the splicing regulator SLM1 provides a mechanism for shaping the molecular repertoires of synaptic adhesion molecules in neuronal populations in vivo.

Cited by 84 publications

References 47 publications

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

Regulation and postsynaptic binding of neurexins — drug targets for neurodevelopmental and neuropsychiatric disorders

Structural investigations of the RNA-binding properties of STAR proteins

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