Disease relevance of Sfrs2

• Here we report that tissue-specific ablation of the splicing factor SC35 in the heart causes dilated cardiomyopathy (DCM) [1].
• The implication of SC35 in heart disease agrees with a recently documented link of SC35 expression to heart failure and interference of splicing regulation during infection by myocarditis-causing viruses [1].
• As a model of species transmission, we used the highly pathogenic avian influenza virus SC35 (H7N7), which is low-pathogenic for mice, and its lethal mouse-adapted descendant SC35M [2].
• In addition, complementation analyses performed with beta-globin or adenovirus E1A transcripts and different splicing-deficient extracts have revealed that SRp46 does not display the same activity as PR264/SC35 [3].
• In contrast, SC-35 remained distributed in a speckled pattern throughout nuclei of dorsal root ganglion neurons and PC12 cells, even in cases where snRNPs were almost exclusively positioned at the nuclear periphery [4].

Psychiatry related information on Sfrs2

• Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. Implications for Alzheimer's disease [5].

High impact information on Sfrs2

• We have also compared the localization of c-fos transcripts with the speckled nuclear regions that are enriched in snRNPs and the non-snRNP splicing factor SC-35 [6].
• We demonstrate that ASF/SF2 and SC35 are each required for cell viability, but, surprisingly, the effector RS domain of ASF/SF2 is dispensable for cell survival in MEFs [7].
• Deletion of SC35 alters alternative splicing of CD45, a receptor tyrosine phosphatase known to be regulated by differential splicing during thymocyte development and activation [8].
• SC35 plays a role in T cell development and alternative splicing of CD45 [8].
• Here we report that Cre-mediated conditional deletion of the prototypical SR protein SC35 in the thymus causes a defect in T cell maturation [8].

Biological context of Sfrs2

• Although SC35 was deleted early in cardiogenesis by using the MLC-2v-Cre transgenic mouse, heart development appeared largely unaffected, with the DCM phenotype developing 3-5 weeks after birth and the mutant animals having a normal life span [1].
• Repositioning of muscle-specific genes relative to the periphery of SC-35 domains during skeletal myogenesis [9].
• There was no apparent change in gene localization relative to either the chromosome territory or the heterochromatic compartment; thus, the gene repositioning seemed to occur specifically with respect to SC-35 domains [9].
• Computer-assisted analysis of MRF-1 revealed substantial sequence homology in the central and the COOH-terminal regions of this protein with the previously identified splicing factor SC35 [10].
• Embryo-derived factors were also implicated in the up-regulation of SC35 mRNA at implantation sites [11].

Anatomical context of Sfrs2

• Accordingly, nucleoplasmic (snRNPs and SC-35) and nucleolar (fibrillarin) splicing factors are more abundant in hepatocyte nuclei of GM-fed than in control mice [12].
• Here, we investigate whether gene organization relative to SC-35 domains is cell type specific by following several muscle and nonmuscle genes in human fibroblasts, committed but proliferative myoblasts, and terminally differentiated muscle [9].
• Although no change was seen for other loci, two muscle genes (Human beta-cardiac myosin heavy chain and myogenin) became localized to the periphery of an SC-35 domain in terminally differentiated muscle nuclei, but not in proliferative myoblasts or in fibroblasts [9].
• We now report the isolation of a recombinant cDNA clone, named myelin regulatory factor-1 (MRF-1) from a mouse brain expression library that encodes a novel protein which interacts with the MB3 domain [10].
• This gene relocation adjacent to a prominent SC-35 domain was recapitulated in mouse 3T3 cells induced into myogenesis by introduction of MyoD [9].

Associations of Sfrs2 with chemical compounds

• The expression of alternatively spliced mRNAs for SC35 was differently regulated both during early pregnancy and by steroid hormones [11].
• The 5' end of E10 contains a previously unrecognized multipartite exon splicing enhancer (ESE) composed of an SC35-like binding sequence, a purine-rich sequence, and an AC-rich element [13].

Enzymatic interactions of Sfrs2

• Furthermore, immunoprecipitated SC35 is phosphorylated by recombinant GSK-3beta [5].

Regulatory relationships of Sfrs2

• It enhanced redistribution of the nuclear polypyrimidine tract-binding protein but had no influence on the localization of the nuclear splicing factor SC-35 [14].

Other interactions of Sfrs2

• Immunofluorescence studies showed that after GSK-3 inhibition, SC35, a member of the SR family, is redistributed and enriched in nuclear speckles and colocalizes with the kinase [5].
• Additionally, the Oct-4 distribution was examined relative to that of the unphosphorylated form of RNA polymerase II (Pol II) and splicing factor (SC 35) in the intranuclear entities such as perichromatin fibrils (PFs), perichromatin granules (PGs), interchromatin granule clusters (IGCs), Cajal bodies (CBs), and nucleolus-like bodies (NLBs) [15].
• Finally, double label immunofluorescence experiments performed with mammalian cells revealed colocalization of mDEAH9 and splicing factor SC35 in punctate nuclear speckles [16].
• These results indicate that p255 and SC-35 are present in the same nuclear structures, to which they are more tightly bound than the snRNP antigens [17].

Analytical, diagnostic and therapeutic context of Sfrs2

• Small nuclear ribonucleoproteins (snRNPs), the splicing factor SC-35, and a protein linked to cell proliferation (p-120) were detected by indirect immunofluorescence. snRNP distribution is consistent with the prophase state of oocyte's nuclei, while SC-35 (and p-120) exhibit a "speckled" distribution throughout the entire period of growth [18].
• We have used in situ hybridization and immunocytochemistry to compare the nuclear localization of a specific nascent pre-mRNA and the essential non-snRNP splicing factor SC-35 [6].
• In undifferentiated PC12 cells and in non-neuronal cells growing in association with dorsal root ganglion neurons, confocal immunocytochemistry revealed a typical, speckled distribution of snRNP aggregates, which colocalized with the SC-35 splicing factor [4].

References