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Results for “splicing variant”

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PubMed1996

Expression of fibronectin mRNA splice variants by rabbit lung in vivo and by alveolar type II cells in vitro.

Fibronectin (FN) is a multidomain glycoprotein with putative functions in tissue development and repair. In repair of alveolar injury, FN may promote the transition of type II epithelial cells to type I epithelial cells. Alternative splicing of FN mRNA, including the EIIIA and EIIIB exons, results in protein isoforms that have cell, tissue, and developmental specificity. The present work found that FN mRNA with the EIIIA exon was in fetal, adult, and oxidant-injured lung. The EIIIB splice variant, however, was restricted to fetal lung and adult lung recovering from oxidant injury. Because alveolar type II cells in vitro express FN, we examined the splice variants in two conditions that induce FN [transforming growth factor-beta 1 (TGF-beta 1) treatment and time in culture]. TGF-beta 1 increased both EIIIA and EIIIB mRNA abundance by 10-fold. Increased EIIIA isoform immunostaining was also noted. Type II cells that spontaneously express FN at 72 h in vitro had increased EIIIA and EIIIB mRNA and increased immunostaining for EIIIA. Nuclear runoff showed induction of FN gene transcription at 72 h in vitro. Together, these data show differential FN splice variant expression in lung, with EIIIB mRNA restricted to fetal and recovering oxidant-injured lung. Furthermore, the transition of type II cells to a type I-like cell is accompanied by increased FN gene transcription and induction of both EIIIA and EIIIB mRNA.

Animals↗

PubMed2004

Analysis of Maxi-K alpha subunit splice variants in human myometrium.

BACKGROUND: Large-conductance, calcium-activated potassium (Maxi-K) channels are implicated in the modulation of human uterine contractions and myometrial Ca2+ homeostasis. However, the regulatory mechanism(s) governing the expression of Maxi-K channels with decreased calcium sensitivity at parturition are unclear. The objectives of this study were to investigate mRNA expression of the Maxi-K alpha subunit, and that of its splice variants, in human non-pregnant and pregnant myometrium, prior to and after labour onset, to determine whether altered expression of these splice variants is associated with decreased calcium sensitivity observed at labour onset. METHODS: Myometrial biopsies were obtained at hysterectomy (non-pregnant, NP), and at Caesarean section, at elective (pregnant not-in-labour, PNL) and intrapartum (pregnant in-labour, PL) procedures. RNA was extracted from all biopsies and quantitative real-time RT-PCR was used to investigate for possible differential expression of the Maxi-K alpha subunit, and that of its splice variants, between these functionally-distinct myometrial tissue sets. RESULTS: RT-PCR analysis identified the presence of a 132 bp and an 87 bp spliced exon of the Maxi-K alpha subunit in all three myometrial tissue sets. Quantitative real-time PCR indicated a decrease in the expression of the Maxi-K alpha subunit with labour onset. While there was no change in the proportion of Maxi-K alpha subunits expressing the 87 bp spliced exon, the proportion of alpha subunits expressing the 132 bp spliced exon was significantly increased with labour onset, compared to both non-pregnant and pregnant not-in-labour tissues. An increased proportion of 132 bp exon-containing alpha subunit variants with labour onset is of interest, as channels expressing this spliced exon have decreased calcium and voltage sensitivities. CONCLUSIONS: Our findings suggest that decreased Maxi-K alpha subunit mRNA expression in human myometrium at labour onset, coupled to an increased proportion of Maxi-K channels expressing the 132 bp spliced exon, may be linked to decreased Maxi-K channel calcium and voltage sensitivity, thereby promoting enhanced uterine activity at the time of labour.

Adult↗

PubMed2005

Regulation of adenylate cyclase type VIII splice variants by acute and chronic Gi/o-coupled receptor activation.

We previously reported that acute agonist activation of G(i/o)-coupled receptors inhibits adenylate cyclase (AC) type VIII activity, whereas agonist withdrawal following chronic activation of these receptors induces AC-VIII superactivation. Three splice variants of AC-VIII have been identified, which are called AC-VIII-A, -B and -C (with AC-VIII-B missing the glycosylation domain and AC-VIII-C lacking most of the C1b area). We report here that AC-VIII-A and -B, but not -C, are inhibited by acute mu-opioid and dopaminergic type D2 receptor activation, indicating that the C1b area of AC-VIII has an important role in AC inhibition by G(i/o)-coupled receptor activation. On the other hand the glycosylation sites in AC-VIII did not play a role in AC-VIII regulation. Although AC-VIII-A and -C differed in their capacity to be inhibited by acute agonist exposure, agonist withdrawal after prolonged treatment led to a similar superactivation of all three splice variants, with no significant change in AC-VIII expression. AC-VIII superactivation was not affected by pre-incubation with a cell permeable cAMP analogue, indicating that the superactivation does not depend on the agonist-induced reduction in cAMP levels. The superactivated AC-VIII-A, -B and -C were similarly re-inhibited by re-application of agonist (morphine or quinpirole), returning the activity to control levels. These results demonstrate marked differences in the agonist inhibition of the AC-VIII splice variants before, but not after, superactivation.

Adenylyl Cyclases↗

PubMed2006

TCRzeta mRNA splice variant forms observed in the peripheral blood T cells from systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology. Tyrosine phosphorylation and protein expression of the T-cell receptor zeta chain (zeta) have been reported to be significantly decreased in SLE T cells. In addition, zeta mRNA with alternatively spliced 3' untranslated region (zetamRNA/as-3'UTR) is detected predominantly in SLE T cells, and aberrant zeta mRNA accompanied by the mutations in the open reading frame including zeta mRNA lacking exon7 (zetamRNA/exon7-) is observed in SLE T cells. These zeta mRNA splice variant forms exhibit a reduction in the expression of TCR/CD3 complex and zeta protein on their cell surface due to the instability of zeta mRNA splice variant forms as well as the reduction in interleukin (IL)-2 production after stimulating with anti-CD3 antibody. Data from cDNA microarray showed that 36 genes encoding cytokines and chemokines, including IL-2, IL-15, IL-18, and TGF-beta2, were down-regulated in the MA5.8 cells transfected with the zeta mRNA splice variant forms. Another 16 genes were up-regulated and included genes associated with membranous proteins and cell damage granules, including the genes encoding poliovirus-receptor-related 2, syndecan-1, and granzyme A.

3' Untranslated Regions↗

PubMed2005

A microarray configuration to quantify expression levels and relative abundance of splice variants.

Over the past decade, alternative RNA splicing has raised a great interest appearing to be of high importance in the generation of expression diversity. This regulatory process plays a critical role in the normal development and its impact on the initiation and development of human disorders as well as on the pharmacological properties of drugs is increasingly being recognized. Only few studies describe specific alternative splicing expression profiling. Microarray strategies have been conceived to address alternative splicing events but with very few experimental data related to their abilities to provide true quantification values. We have developed a specific microarray configuration relying on a few, well optimized probes per splice event. Basically, five probes of 24mer are used to fully characterize a splice event. These probes are of two types, exon probes and junction probes, and are either specific to a splice event or not. The performances of such a 'splice array' were validated on synthetic model systems and on complex biological materials. The results indicate that DNA chips based on this design combining exon and junction derived probes enable the detection and, absolute and relative quantification of splice variants. In addition, this strategy is compatible with all the microarrays that use oligonucleotide probes.

Alternative Splicing↗

PubMed1999

Novel brain-specific 5-HT4 receptor splice variants show marked constitutive activity: role of the C-terminal intracellular domain.

We have cloned new 5-Hydroxytryptamine 4 (5-HT4) receptor splice variants from mouse (m5-HT4(e)R and m5-HT4(f)R), rat (r5-HT4(e)R), and human brain tissue (h5-HT4(e)R) which differ, as do the previously described 5-HT4 receptor variants, in the length and composition of their intracellular C termini after the common splicing site (L358). These new variants have a unique C-terminal sequence made of two PV repeats and are only expressed in brain tissue. All of the 5-HT4 receptor splice variants have a high constitutive activity when expressed at low and physiological densities (<500 fmol/mg protein). At similar density, they showed a much higher constitutive activity than the native and the mutated beta2-adrenergic receptors. The constitutive activity of the new splice variants with short C-terminal sequences (m5-HT4(e)R and m5-HT4(f)R) was higher than that of the long C-terminal sequence variants (m5-HT4(a)R and m5-HT4(b)R). This may indicate that the short variants have a higher capacity for isomerization from the inactive to the active conformation. Moreover, we further identified a sequence within the C-terminal tail upstream of L358, rich in serine and threonine residues, that played a crucial role in maintaining 5-HT4R under its inactive conformation.

Alternative Splicing↗

PubMed2002

Quantitative measurement of the splice variants 120 and 164 of the angiogenic peptide vascular endothelial growth factor in the time flow of fracture healing: a study in the rat.

Formation of new blood vessels is essential for the process of wound and fracture healing. Little is known about the time-dependent expression and the involved splice variants of the vascular endothelial growth factor (VEGF). We therefore quantified and differentiated the angiogenic factor VEGF and its receptors (VEGFR) in a rat fracture model by immunohistochemical, biochemical and molecular biological methods. VEGF could be immunostained in chondrocytes and osteoblasts of the callus, but not in fibrous callus. In the capillaries, VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR) were also visualized. Both receptors were also detectable in some chondrocytes and in osteoclasts. Enzyme-linked immunosorbent assay (ELISA) measurements showed high levels of VEGF in fractured tibiae and negligible ones in non-injured bone. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed expression of the rat splice variants VEGF(120) and VEGF(164) during the course of fracture healing, which corresponds to human VEGF121 and VEGF165 splice variants. VEGF plays the most important role during the early phase of fracture healing, but VEGF concentrations decrease further after day 5.

Alternative Splicing↗

PubMed2006

Cells expressing murine RAD52 splice variants favor sister chromatid repair.

The RAD52 gene is essential for homologous recombination in the yeast Saccharomyces cerevisiae. RAD52 is the archetype in an epistasis group of genes essential for DNA damage repair. By catalyzing the replacement of replication protein A with Rad51 on single-stranded DNA, Rad52 likely promotes strand invasion of a double-stranded DNA molecule by single-stranded DNA. Although the sequence and in vitro functions of mammalian RAD52 are conserved with those of yeast, one difference is the presence of introns and consequent splicing of the mammalian RAD52 pre-mRNA. We identified two novel splice variants from the RAD52 gene that are expressed in adult mouse tissues. Expression of these splice variants in tissue culture cells elevates the frequency of recombination that uses a sister chromatid template. To characterize this dominant phenotype further, the RAD52 gene from the yeast Saccharomyces cerevisiae was truncated to model the mammalian splice variants. The same dominant sister chromatid recombination phenotype seen in mammalian cells was also observed in yeast. Furthermore, repair from a homologous chromatid is reduced in yeast, implying that the choice of alternative repair pathways may be controlled by these variants. In addition, a dominant DNA repair defect induced by one of the variants in yeast is suppressed by overexpression of RAD51, suggesting that the Rad51-Rad52 interaction is impaired.

3T3 Cells↗

PubMed2004

Alternate splice variants of mouse NR2B gene.

Two alternate spliced transcripts of N-methyl-D-aspartate receptor (NR2B) gene derived from a common promoter have been reported earlier. In the present study, we have examined the expression of alternative splice variants of NR2B gene using 5' rapid amplification of C terminal end (RACE) in the RNA derived from mouse cortex. RT-PCR was performed to confirm the RACE data. Here we report the occurrence of three transcripts containing a novel alternate spliced exon, we refer to as exon 1'. This new exon is located upstream of the transcription start site identified by Klein et al. [Gene 208 (1998) 259] in the 5' untranslated region (UTR) of NR2B, thus making a new alternate 5' end of the NR2B transcript. The molecular nature of the transcripts containing the new exon appears to be highly heterogeneous. These results are interesting in that they are of potential importance in translational regulation of the NR2B gene.

5' Untranslated Regions↗

PubMed2005

Synaptic targeting of N-methyl-D-aspartate receptor splice variants is regulated differentially by receptor activity.

The formation of postsynaptic clusters of various ligand-gated ion channels is regulated by receptor activity. Here we describe the developmental- and activity-dependent modification of N-methyl-D-aspartate (NMDA) receptor clustering in spinal cord neurons in vitro detected by immunofluorescence analysis using subunit and splice variant specific antibodies. NMDA receptors form synaptic and extrasynaptic clusters with sequential changes in subunit composition during in vitro development. During the first week of in vitro culture, a NR1 splice variant containing the C2-carboxy terminus and lacking the N1-cassette and the NR2B subunit are the prevailing components of receptor clusters at synaptic and extrasynaptic sites. After 3 weeks in culture (days in vitro [DIV] 22), the numbers of postsynaptic receptor clusters with N1-containing NR1 splice variants and NR2A subunits are upregulated. At DIV22, C2-specific clusters are abundant and are predominantly localized at postsynaptic sites, whereas the total number of C2'-clusters in dendrites is much lower and these clusters are localized mostly extrasynaptically. However, upon chronic inhibition of NMDA receptor activity in DIV8 and DIV22 cultures with MK801, the number of postsynaptic NR1-C2' subunit clusters is strongly upregulated. In contrast, numbers of NR1-C2 clusters are only modestly increased in DIV8 and not changed in DIV22 cultures upon MK801 treatment, suggesting a specific role of NR1 carboxy-terminal sequences in the activity-dependent synaptic targeting of NMDA receptor clusters of spinal cord neurons.

Alternative Splicing↗

PubMed2003

TRAIL-beta and TRAIL-gamma: two novel splice variants of the human TNF-related apoptosis-inducing ligand (TRAIL) without apoptotic potential.

Tumour necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL/APO2L) is a recently identified member of the TNF family, which induces programmed cell death in a variety of neoplastic cell types, but not in most nonneoplastic cells. In this study, we report on the identification of two novel alternative splice variants of TRAIL in neoplastic and non-neoplastic human cells lacking either exon 3 (TRAIL-beta) or exons 2 and 3 (TRAIL-gamma). In both splice variants, loss of exon 3 resulted in a frame shift generating a stop codon with consecutive extensive truncation in the extracellular domain. Ectopic expression revealed a loss of proapoptotic potential for both alternative splice variants. In contrast to the predominantly cytoplasmatic localisation of GFP-tagged TRAIL-alpha and TRAIL-beta, TRAIL-gamma showed an additional association with the cell surface and nuclear membrane. In conclusion, alternative splicing might be involved in fine tuning of TRAIL-induced apoptosis and underlines the complexity of the TRAIL system.

Alternative Splicing↗

PubMed2001

Human Ca2+/calmodulin-dependent phosphodiesterase PDE1A: novel splice variants, their specific expression, genomic organization, and chromosomal localization.

We report here the identification of novel human PDE1A splice variants, their tissue distribution patterns, genomic structure, and chromosomal localization of the gene. We identified one N-terminus (N3) and one C-terminus (C3) by cDNA library screening and dbEST database search. These N- and C-termini, including the reported N-termini (N1 and N2) and C-termini (C1 and C2), combined to generate nine different PDE1A cDNAs. N1 and N2 are similar to the 5' ends of the bovine PDE1A proteins of 61 kDa and 59 kDa, respectively, and C1 and C2 are the 3' ends of the reported human PDE1A variants. The results of PCR and Southern blot analysis show that nine PDE1A splice variants exhibit distinctive tissue distribution patterns by the difference of the N-terminus. PDE1As with N2 were widely expressed in various tissues, mainly in the kidney, liver, and pancreas. On the other hand, PDE1As with N1 and N3 were particularly expressed at a high level in the brain and testis, respectively. These findings suggest that the distinct expression patterns among PDE1A variants depend on the several promoters situated upstream of exons encoding 5' ends of the variants. The PDE1A gene spans over 120 kb of genomic DNA, and consists of at least 17 exons and 16 introns. The PDE1A gene was located on human chromosome 2q32 by fluorescent in situ hybridization analysis.

Amino Acid Sequence↗

PubMed1998

Expression of an embryonic fibronectin splicing variant in human masseter muscle.

Fibronectin is an extracellular matrix protein that is a key constituent of all skeletal muscles. Its deposition increases in a number of pathological conditions, including some muscular dystrophies in which a progressive increase in lower-face height is often noted. It has been shown in other organ systems that increased deposition of fibronectin is associated with changes in the expression of differentially spliced isoforms of the molecule. This investigation documents the expression of mRNA coding for fibronectin and its splicing variants, EIIIA and EIIIB, in biopsies of masseter muscle from normal and long-face patients, using reverse transcriptase-polymerase chain reaction. Expression was compared with that occurring in anatomically and embryologically differing somatic skeletal muscle. Masseter expressed fibronectin mRNA containing the EIIIA but not the EIIIB splicing variant. Conversely, somatic skeletal muscle expressed neither the EIIIA nor EIIIB variants. There were no differences between expression of fibronectin containing the EIIIA splicing variants in masseter from normal and long faces. These results suggest that variations in fibronectin expression reflect the differing functional demands of muscles from different anatomical locations and indicate that jaw and somatic muscle belong to different allotypes.

Base Sequence↗

PubMed2003

Phosphorylation of type-1 inositol 1,4,5-trisphosphate receptors by cyclic nucleotide-dependent protein kinases: a mutational analysis of the functionally important sites in the S2+ and S2- splice variants.

Inositol 1,4,5-trisphosphate receptors (InsP3R) are the major route of intracellular calcium release in eukaryotic cells and as such are pivotal for stimulation of Ca2+-dependent effectors important for numerous physiological processes. Modulation of this release has important consequences for defining the particular spatio-temporal characteristics of Ca2+ signals. In this study, regulation of Ca2+ release by phosphorylation of type-1 InsP3R (InsP3R-1) by cAMP (PKA)- and cGMP (PKG)-dependent protein kinases was investigated in the two major splice variants of InsP3R-1. InsP3R-1 was expressed in DT-40 cells devoid of endogenous InsP3R. In cells expressing the neuronal, S2+ splice variant of the InsP3R-1, Ca2+ release was markedly enhanced when either PKA or PKG was activated. The sites of phosphorylation were investigated by mutation of serine residues present in two canonical phosphorylation sites present in the protein. Potentiated Ca2+ release was abolished when serine 1755 was mutated to alanine (S1755A) but was unaffected by a similar mutation of serine 1589 (S1589A). These data demonstrate that Ser-1755 is the functionally important residue for phosphoregulation by PKA and PKG in the neuronal variant of the InsP3R-1. Activation of PKA also resulted in potentiated Ca2+ release in cells expressing the non-neuronal, S2- splice variant of the InsP3R-1. However, the PKA-induced potentiation was still evident in S1589A or S1755A InsP3R-1 mutants. The effect was abolished in the double (S1589A/S1755A) mutant, indicating both sites are phosphorylated and contribute to the functional effect. Activation of PKG had no effect on Ca2+ release in cells expressing the S2- variant of InsP3R-1. Collectively, these data indicate that phosphoregulation of InsP3R-1 has dramatic effects on Ca2+ release and defines the molecular sites phosphorylated in the major variants expressed in neuronal and peripheral tissues.

Alternative Splicing↗

PubMed2001

Novel activator protein-2alpha splice-variants function as transactivators of the ovine placental lactogen gene.

Activator protein-2 (AP-2) has been implicated as a transactivator of the human and ovine placental lactogen (oPL) genes. Transcriptional enhancement through an AP-2 cis-acting element has been described for other genes expressed in the placenta, but the AP-2 isoform enhancing expression is species dependent. Transactivation of the oPL minimal promoter (-124 bp to +16 bp) by AP-2 was confirmed by mutational analysis in transiently transfected human choriocarcinoma cells (BeWo). AP-2alpha was localized in ovine chorionic epithelial cells by immunohistochemistry and a 3-kb transcript was identified by Northern hybridization. Four nearly full-length AP-2 cDNAs were isolated from an ovine placenta cDNA library. Nucleotide sequencing these cDNAs revealed that the AP-2 mRNA expressed in the ovine placenta shares identity with human AP-2alpha, but variations in the predicted N-terminus were observed, and three unique AP-2alpha splice-variants were identified. Expression of AP-2alpha variants in HepG2 cells, devoid of endogenous AP-2, indicates that enhancement through the AP-2 element in the oPL gene minimal promoter was variant dependent. RNA transcripts for all of the ovine AP-2alpha splice-variants were confirmed in ovine placenta by RT-PCR, and homologs for two variants were found in human placenta. However, only one AP-2alpha transcript, which shares identity to Xenopus AP-2alpha, was expressed in BeWo cells. Immunoblot analysis confirmed AP-2alpha variants in ovine chorionic binucleate cell nuclear extracts, one of which migrates similar to the AP-2alpha variant identified in BeWo cell nuclear extracts. These data indicate the presence of new mammalian AP-2alpha splice-variants that augment transactivation of the oPL gene in ovine chorionic binucleate cells.

Alternative Splicing↗

PubMed2006

TRAIL-R4-beta: a new splice variant of TRAIL-receptor 4 lacking the cysteine rich domain 1.

Transcriptional modification by alternative splicing is known to be involved in the regulation of programmed cell death. Recently, alternative splice variants of the TNF-related apoptosis inducing ligand (TRAIL/APO2L) and of the death receptor TRAIL-R2/DR5 have been identified. In this study, we report the identification of a novel alternative splice variant of the decoy receptor with a truncated death domain TRAIL-R4 lacking exon 3, which we designated TRAIL-R4-beta. As revealed by BLAST search we identified the genomic organisation of the TRAIL-R4 gene which consists of 9 exons. Loss of exon 3 resulted in the truncation of the first complete cysteine rich domain 1 which is known to be involved in ligand-receptor-complex. In conclusion, alternative splicing might be involved in functional fine-tuning of TRAIL-induced programmed cell death.

Alternative Splicing↗

PubMed2001

Identification of three new splice variants of the SNARE protein SNAP-23.

SNAP-23 has an important role in protein-trafficking processes in mammalian cells and until yet two isoforms of SNAP-23 (SNAP-23a and SNAP-23b) have been described. In the present report, we have identified the existence of three new SNAP-23 isoforms (named SNAP-23c, SNAP-23d, and SNAP-23e), which arise from alternative splicing. By RT-PCR all five splice variants were shown to be expressed in four different human inflammatory cells (eosinophils, basophils, neutrophils, and peripheral blood mononuclear cells). Transfection of the human basophilic KU-812 cell line with plasmid constructs containing the cDNAs of the five splice variants located SNAP-23a and SNAP-23b primarily in the plasma membrane. The other three splice variants were localized both intracellularly and in the plasma membrane.

Alternative Splicing↗

PubMed2004

Three new alternative splicing variants of human cytochrome P450 2D6 mRNA in human extratumoral liver tissue.

AIM: To identify the new alternative splicing variants of human CYP2D6 in human extratumoral liver tissue with RT-PCR and sequencing. METHODS: Full length of human CYP2D6 cDNAs was amplificated by reverse transcription-polymerase chain reaction (RT-PCR) from a human extratumoral liver tissue and cloned into pGEM-T vector. The cDNA was sequenced. Exons from 1 to 4 of human CYP2D6 cDNAs were also amplificated by RT-PCR from extratumoral liver tissues of 17 human hepatocellular carcinomas. Some RT-PCR products were sequenced. Exons 1 to 4 of CYP2D6 gene were amplified by PCR from extratumoral liver tissue DNA. Two PCR products from extratumoral liver tissues expressing skipped mRNA were partially sequenced. RESULTS: One of the CYP2D6 cDNAs had 470 nucleotides from 79 to 548 (3' portion of exons 1 to 5' portion of exon 4), and was skipped. Exons 1 to 4 of CYP2D6 cDNA were assayed with RT-PCR in 17 extratumoral liver tissues. Both wild type and skipped mRNAs were expressed in 4 samples, only wild type mRNA was expressed in 5 samples, and only skipped mRNA was expressed in 8 samples. Two more variants were identified by sequencing the RT-PCR products of exons 1 to 4 of CYP2D6 cDNA. The second variant skipped 411 nucleotides from 175 to 585. This variant was identified in 4 different liver tissues by sequencing the RT-PCR products. We sequenced partially 2 of the PCR products amplified of CYP2D6 exon 1 to exon 4 from extratumoral liver tissue genomic DNA that only expressed skipped mRNA by RT-PCR. No point mutations around exon 1, intron 1, and exon 4, and no deletion in CYP2D6 gene were detected. The third variant was the skipped exon 3 , and 153 bp was lost. CONCLUSION: Three new alternative splicing variants of CYP2D6 mRNA have been identified. They may not be caused by gene mutation and may lose CYP2D6 activity and act as a down-regulator of CYP2D6.

Alternative Splicing↗